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Laabi S, LeMmon C, Vogel C, Chacon M, Jimenez VM. Psilocybin and psilocin regulate microglial immunomodulation and support neuroplasticity via serotonergic and AhR signaling. Int Immunopharmacol 2025; 159:114940. [PMID: 40424654 DOI: 10.1016/j.intimp.2025.114940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/22/2025] [Accepted: 05/20/2025] [Indexed: 05/29/2025]
Abstract
BACKGROUND Psilocybin, a serotonergic psychedelic, has demonstrated therapeutic potential in neuropsychiatric disorders. While its neuroplastic and immunomodulatory effects are recognized, the underlying mechanisms remain unclear. This study investigates how psilocybin and its active metabolite, psilocin, influence microglial inflammatory responses and neurotrophic factor expression through serotonergic and AhR signaling. METHODS Using in vitro models of resting and LPS-activated microglia, we evaluated the effects of psilocybin and psilocin on the expression of pro-inflammatory cytokines (TNF-α), anti-inflammatory cytokines (IL-10), and neuroplasticity-related markers (BDNF). Receptor-specific contributions were assessed using selective antagonists for 5-HT2A, 5-HT2B, 5-HT7, TrkB, and AhR. RESULTS Psilocybin and psilocin significantly suppressed TNF-α expression and increased BDNF levels in LPS-activated microglia. These effects were mediated by 5-HT2A, 5-HT2B, 5-HT7, and TrkB signaling, while AhR activation was required for psilocin-induced BDNF upregulation but not TNF-α suppression. IL-10 levels remained unchanged under normal conditions but increased significantly when serotonergic, TrkB, or AhR signaling was blocked, suggesting a compensatory shift in anti-inflammatory pathways. CONCLUSION Psilocybin and psilocin promote a microglial phenotype that reduces inflammation and supports neuroplasticity via receptor-specific mechanisms. Their effects on TNF-α and BDNF depend on distinct serotonergic and neurotrophic pathways, with AhR playing a selective role in psilocin's action. These findings clarify the receptor-mediated dynamics of psilocybin's therapeutic effects and highlight alternative anti-inflammatory pathways that may be relevant for clinical applications.
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Affiliation(s)
- Salma Laabi
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, 2162 S 180 E, Provo, UT 84606, United States
| | - Claire LeMmon
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, 2162 S 180 E, Provo, UT 84606, United States
| | - Callie Vogel
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, 2162 S 180 E, Provo, UT 84606, United States
| | - Mariana Chacon
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, 2162 S 180 E, Provo, UT 84606, United States
| | - Victor M Jimenez
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, 2162 S 180 E, Provo, UT 84606, United States; Department of Pharmacy, Roseman University of Health Sciences, 10920 S River Front Pkwy, South Jordan, UT 84095, United States.
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Priebe T, Subkhangulova A, Toonen RF, Verhage M. Neuronal network inactivity potentiates neuropeptide release from mouse cortical neurons. eNeuro 2025; 12:ENEURO.0555-24.2024. [PMID: 40101959 PMCID: PMC11964291 DOI: 10.1523/eneuro.0555-24.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 12/20/2024] [Accepted: 12/24/2024] [Indexed: 03/20/2025] Open
Abstract
Neurons adapt to chronic activity changes by modifying synaptic properties, including neurotransmitter release. However, whether neuropeptide release via dense core vesicles (DCVs)-a distinct regulated secretory pathway-undergoes similar adaptation remains unclear. Here, we demonstrate that 24-hour action potential blockade leads to significant DCV accumulation in primary mouse cortical neurons of both sexes. Reactivation with action potential trains induced enhanced Ca2+-influx and 700% more DCV exocytosis compared to control neurons. Notably, total DCV cargo protein levels were unchanged, while mRNA levels of corresponding genes were reduced. Blocking neurotransmitter release with Tetanus toxin induced DCV accumulation, similar to that induced by network silencing with TTX. Hence, chronic network silencing triggers increased DCV accumulation due to reduced exocytosis during silencing. These accumulated DCVs can be released upon reactivation resulting in a massive potentiation of DCV exocytosis, possibly contributing to homeostatic mechanisms.Significance Statement This study addresses an unexplored area - how dense core vesicles (DCVs) exocytosis adapts to chronic changes in activity - and demonstrates accumulation of DCVs and a massive upregulation of DCV exocytosis in response to 24h inactivity. The potentiation of neuropeptide release might contribute to homeostatic regulation of neuronal networks in the brain.
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Affiliation(s)
- Theresa Priebe
- Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neurosciences Campus Amsterdam, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Aygul Subkhangulova
- Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neurosciences Campus Amsterdam, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Ruud F Toonen
- Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neurosciences Campus Amsterdam, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Matthijs Verhage
- Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neurosciences Campus Amsterdam, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands;
- Department of Human Genetics, Center for Neurogenomics and Cognitive Research, Neurosciences Campus Amsterdam, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands
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Imamichi T, Yang J, Chen Q, Goswami S, Marquez M, Kariyawasam U, Sharma HN, Wiscovitch-Russo R, Li X, Aioi A, Adelsberger JW, Chang W, Higgins J, Sui H. Interleukin-27-polarized HIV-resistant M2 macrophages are a novel subtype of macrophages that express distinct antiviral gene profiles in individual cells: implication for the antiviral effect via different mechanisms in the individual cell-dependent manner. Front Immunol 2025; 16:1550699. [PMID: 40129989 PMCID: PMC11931227 DOI: 10.3389/fimmu.2025.1550699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 02/17/2025] [Indexed: 03/26/2025] Open
Abstract
Introduction Interleukin (IL)-27 is an anti-viral cytokine. IL-27-treated monocyte-derived macrophages (27-Mac) suppressed HIV replication. Macrophages are generally divided into two subtypes, M1 and M2 macrophages. M2 macrophages can be polarized into M2a, M2b, M2c, and M2d by various stimuli. IL-6 and adenosine induce M2d macrophages. Since IL-27 is a member of the IL-6 family of cytokines, 27-Mac was considered M2d macrophages. In the current study, we compared biological function and gene expression profiles between 27-Mac and M2d subtypes. Methods Monocytes derived from health donors were differentiated to M2 using macrophage colony-stimulating factor. Then, the resulting M2 was polarized into different subtypes using IL-27, IL-6, or BAY60-658 (an adenosine analog). HIV replication was monitored using a p24 antigen capture assay, and the production of reactive oxygen species (ROS) was determined using a Hydrogen Peroxide Assay. Phagocytosis assay was run using GFP-labeled opsonized E. coli. Cytokine production was detected by the IsoPlexis system, and the gene expression profiles were analyzed using single-cell RNA sequencing (scRNA-seq). Results and Discussion 27-Mac and BAY60-658-polarized M2d (BAY-M2d) resisted HIV infection, but IL-6-polarized M2d (6-M2d) lacked the anti-viral effect. Although phagocytosis activity was comparable among the three macrophages, only 27-Mac, but neither 6-M2d nor BAY-M2d, enhanced the generation of ROS. The cytokine-producing profile of 27-Mac did not resemble that of the two subtypes. The scRNA-seq revealed that 27-Mac exhibited a different clustering pattern compared to other M2ds, and each 27-Mac expressed a distinct combination of anti-viral genes. Furthermore, 27-Mac did not express the biomarkers of M2a, M2b, and M2c. However, it significantly expressed CD38 (p<0.01) and secreted CXCL9 (p<0.001), which are biomarkers of M1. Conclusions These data suggest that 27-Mac may be classified as either an M1-like subtype or a novel subset of M2, which resists HIV infection mediated by a different mechanism in individual cells using different anti-viral gene products. Our results provide a new insight into the function of IL-27 and macrophages.
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Affiliation(s)
- Tomozumi Imamichi
- Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Jun Yang
- Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Qian Chen
- Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Suranjana Goswami
- Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Mayra Marquez
- Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Udeshika Kariyawasam
- Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Homa Nath Sharma
- Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Rosana Wiscovitch-Russo
- Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Xuan Li
- Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Akihiro Aioi
- Laboratory of Basic Research, Septem-Soken, Osaka, Japan
| | - Joseph W. Adelsberger
- AIDS Monitoring Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Weizhong Chang
- Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Jeanette Higgins
- AIDS Monitoring Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Hongyan Sui
- Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
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Spero V, Scherma M, D'Amelio S, Collu R, Dedoni S, Camoglio C, Siddi C, Fratta W, Molteni R, Fadda P. Activity-based anorexia (ABA) model: Effects on brain neuroinflammation, redox balance and neuroplasticity during the acute phase. Neurochem Int 2024; 180:105842. [PMID: 39244038 DOI: 10.1016/j.neuint.2024.105842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 08/14/2024] [Accepted: 08/25/2024] [Indexed: 09/09/2024]
Abstract
Several evidences suggest that immuno-inflammatory responses are involved in the pathogenesis of anorexia nervosa (AN). Herein we investigate the possible alteration of key mediators of inflammation, redox balance, and neuroplasticity in the brain of rats showing an anorexic-like phenotype. We modeled AN in adolescent female rats using the activity-based anorexia (ABA) paradigm and measured gene expression levels of targets of interest in the prefrontal cortex (PFC) and dorsal hippocampus (DH). We observed reduced mRNA levels of pro-inflammatory cytokines IL-1β and TNF-α, the inflammasome NLRP3, and the microglial marker CD11b in both PFC and DH of ABA animals. Conversely, the mRNA of IL-6, which acts as both a pro-inflammatory and anti-inflammatory cytokine, was increased. Moreover, we observed an overall upregulation of different antioxidant enzymes in PFC, while their profile was not affected or opposite in the DH, with the exception of MT1α. Interestingly, ABA animals showed elevated levels of the neuroplasticity marker BDNF in both PFC and DH. Our data indicate that ABA induction is associated with anatomical-specific cerebral alteration of mediators of neuroinflammation, oxidative balance and neuroplasticity. Although more research should be conducted, these results add important information about the role of these systems in the complex AN etiopathogenesis.
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Affiliation(s)
- Vittoria Spero
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Maria Scherma
- Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy
| | - Sabrina D'Amelio
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Roberto Collu
- Department of Pharmacology, Physiology and Biophysics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Geriatric Research Education and Clinical Center, Bedford VA Healthcare System, Bedford, MA, USA
| | - Simona Dedoni
- Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy
| | - Chiara Camoglio
- Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy
| | - Carlotta Siddi
- Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy
| | - Walter Fratta
- Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy
| | - Raffaella Molteni
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Paola Fadda
- Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy; CNR Institute of Neuroscience - Cagliari, National Research Council, Cagliari, Italy.
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Fukuchi M, Shibasaki Y, Akazawa Y, Suzuki-Masuyama H, Takeuchi KI, Iwazaki Y, Tabuchi A, Tsuda M. Neuron-selective and activity-dependent splicing of BDNF exon I-IX pre-mRNA. Neurochem Int 2024; 181:105889. [PMID: 39455010 DOI: 10.1016/j.neuint.2024.105889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 10/04/2024] [Accepted: 10/22/2024] [Indexed: 10/28/2024]
Abstract
Brain-derived neurotrophic factor (BDNF) is essential for numerous neuronal functions, including learning and memory. The expression of BDNF is regulated by distinctive transcriptional and post-transcriptional mechanisms. The Bdnf gene in mice and rats comprises eight untranslated exons (exons I-VIII) and one exon (exon IX) that contains the pre-proBDNF coding sequence. Multiple splice donor sites on the untranslated exons and a single acceptor site upstream of the coding sequence result in the characteristic exon skipping patterns that generate multiple Bdnf mRNA variants, which are essential for the spatiotemporal regulation of BDNF expression, mRNA localization, mRNA stability, and translational control. However, the regulation of Bdnf pre-mRNA splicing remains unclear. Here, we focused on the splicing of Bdnf exon I-IX pre-mRNA. We first constructed a minigene to evaluate Bdnf exon I-IX pre-mRNA splicing. Compared with Bdnf exon I-IX pre-mRNA splicing in non-neuronal NIH3T3 cells, splicing was preferentially observed in primary cultures of cortical neurons. Additionally, a series of overexpression and knockdown experiments suggested that neuro-oncological ventral antigen (NOVA) 2 is involved in the neuron-selective splicing of Bdnf exon I-IX pre-mRNA. Supporting this finding, endogenous Nova2 mRNA expression was markedly higher in neurons, and a strong correlation between endogenous Bdnf exon I-IX and Nova2 mRNA was observed across several brain regions. Furthermore, Bdnf exon I-IX pre-mRNA splicing was facilitated by Ca2+ signals evoked via L-type voltage-dependent Ca2+ channels. Notably, among the Bdnf pre-mRNA splicing investigated in the current study, neuron-selective and activity-dependent splicing was observed in Bdnf exon I-IX pre-mRNA. In conclusion, Bdnf exon I-IX pre-mRNA splicing is preferentially observed in neurons and is facilitated in an activity-dependent manner. The neuron-selective and activity-dependent splicing of Bdnf exon I-IX pre-mRNA may contribute to the efficient induction of Bdnf exon I-IX expression in neurons.
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Affiliation(s)
- Mamoru Fukuchi
- Laboratory of Molecular Neuroscience, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki, Gunma, 370-0033, Japan; Laboratory of Molecular Neurobiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
| | - Yumi Shibasaki
- Laboratory of Molecular Neuroscience, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki, Gunma, 370-0033, Japan
| | - Yuto Akazawa
- Laboratory of Molecular Neuroscience, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki, Gunma, 370-0033, Japan
| | - Hitoshi Suzuki-Masuyama
- Laboratory of Molecular Neurobiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Ken-Ichi Takeuchi
- Laboratory of Molecular Neurobiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Yumika Iwazaki
- Laboratory of Molecular Neurobiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Akiko Tabuchi
- Laboratory of Molecular Neurobiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Masaaki Tsuda
- Laboratory of Molecular Neurobiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
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He L, Mo X, He L, Ma Q, Cai L, Zheng Y, Huang L, Lin X, Wu M, Ding W, Zhou C, Zhang JC, Hashimoto K, Yao W, Chen JX. The role of BDNF transcription in the antidepressant-like effects of 18β-glycyrrhetinic acid in a chronic social defeat stress model. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 132:155332. [PMID: 38851983 DOI: 10.1016/j.phymed.2023.155332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 12/21/2023] [Accepted: 12/30/2023] [Indexed: 06/10/2024]
Abstract
BACKGROUND Xiaoyaosan (XYS), a traditional Chinese medicine formulation, has been used in the treatment of depression. However, no studies have yet identified the active compounds responsible for its antidepressant effects in the brain. STUDY DESIGN We investigated the antidepressants effects of XYS and identified 18β-glycyrrhetinic acid (18β-GA) as the primary compound present in the brain following XYS injection. Furthermore, we explored the molecular mechanisms underlying the antidepressant-like effects of both XYS and 18β-GA. METHODS To investigate the antidepressant-like effects of XYS and elucidate the associated molecular mechanisms, we employed various methodologies, including cell cultures, the chronic social defeat stress (CSDS) model, behavioral tests, immunoprecipitation, quantitative PCR (qPCR) assays, Western blotting assays, luciferase assays, chromatin immunoprecipitation (ChIP) assays, immunofluorescence staining, and dendritic spine analysis. RESULTS We identified 18β-GA as the primary compound in the brain following XYS injection. In vitro, 18β-GA was found to bind with ERK (extracellular signal-regulated kinase), subsequently activating ERK kinase activity toward both c-Jun and cAMP response element binding protein (CREB). Moreover, 18β-GA activated brain-derived neurotrophic factor (BDNF) transcription by stimulating nuclear factor-erythroid factor 2-related factor 2 (Nrf2), c-Jun, and CREB, while also inhibiting methyl CpG binding protein 2 (MeCP2) both in vitro and in vivo. Chronic intraperitoneal (i.p.) administration of 18β-GA exhibited prophylactic antidepressant-like effects in a CSDS model, primarily by activating BDNF transcription in the medial prefrontal cortex (mPFC). Interestingly, a single i.p. injection of 18β-GA produced rapid and sustained antidepressant-like effects in CSDS-susceptible mice by engaging the BDNF-tropomyosin receptor kinase B (TrkB) signaling pathway in the mPFC. CONCLUSION These findings suggest that the activation of BDNF transcription in the mPFC underlies the antidepressant-like effects of 18β-GA, a key component of XYS in the brain.
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Affiliation(s)
- Lujuan He
- Guangzhou Key Laboratory of Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, PR China; Department of Physiology, School of Medicine, Jinan University, Guangzhou, 510632, PR China
| | - Xiaowei Mo
- Guangzhou Key Laboratory of Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, PR China
| | - Liangliang He
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China
| | - Qingyu Ma
- Guangzhou Key Laboratory of Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, PR China
| | - Lili Cai
- Department of Mental Rehabilitation, Mental Hospital of Guangzhou Civil Affairs Bureau, Guangzhou 510632, PR China
| | - Yi Zheng
- Department of Physiology, School of Medicine, Jinan University, Guangzhou, 510632, PR China
| | - Lixuan Huang
- Department of Physiology, School of Medicine, Jinan University, Guangzhou, 510632, PR China
| | - Xuanyu Lin
- Department of Physiology, School of Medicine, Jinan University, Guangzhou, 510632, PR China
| | - Mansi Wu
- Guangzhou Key Laboratory of Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, PR China
| | - Wanzhao Ding
- Department of Physiology, School of Medicine, Jinan University, Guangzhou, 510632, PR China
| | - Chan Zhou
- Department of Physiology, School of Medicine, Jinan University, Guangzhou, 510632, PR China
| | - Ji-Chun Zhang
- Department of Physiology, School of Medicine, Jinan University, Guangzhou, 510632, PR China
| | - Kenji Hashimoto
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan
| | - Wei Yao
- Guangzhou Key Laboratory of Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, PR China.
| | - Jia-Xu Chen
- Guangzhou Key Laboratory of Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, PR China; School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, PR China.
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Wu Y, Zhu Z, Lan T, Li S, Li Y, Wang C, Feng Y, Mao X, Yu S. Levomilnacipran Improves Lipopolysaccharide-Induced Dysregulation of Synaptic Plasticity and Depression-Like Behaviors via Activating BDNF/TrkB Mediated PI3K/Akt/mTOR Signaling Pathway. Mol Neurobiol 2024; 61:4102-4115. [PMID: 38057644 DOI: 10.1007/s12035-023-03832-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 11/24/2023] [Indexed: 12/08/2023]
Abstract
Depression is a common psychological disease with high morbidity and mortality. Recently, the involvement of synaptic plasticity in the pathogenesis of depression has shed light on the direction of developing novel antidepressants. Levomilnacipran is a newly approved medication for the treatment of adult major depressive disorder. However, the detailed mechanisms underlying its antidepressant-like effects have yet to be illuminated. In this study, we aimed to investigate the role of levomilnacipran in regulating synaptic plasticity and explore the possible molecular mechanisms of its antidepressant effects using a rat model of depression induced by lipopolysaccharide (LPS). The results demonstrated that levomilnacipran (30 mg/kg, i.p.) significantly ameliorated depression-like behaviors in rats, alleviated the dysregulation of synaptic plasticity, and suppressed neuroinflammation within hippocampus induced by LPS-treatment. Levomilnacipran increased the expression of postsynaptic dense 95 (PSD-95) and synaptophysin (Syn) and reversed the imbalance between pro- and anti-inflammatory cytokines within hippocampus of depressed rats. Additionally, levomilnacipran elevated expression level of brain-derived neurotrophic factor (BDNF), accompanied by increased tyrosine kinase B (TrkB), phosphorylated phosphatidylinositol 3-kinase (PI3K), phosphorylated protein kinase B (p-Akt), and phosphorylated mammalian target of rapamycin (p-mTOR). Taken together, these results suggest that levomilnacipran may exert antidepressant effects via upregulating BDNF/TrkB mediated PI3K/Akt/mTOR signaling pathway to improve synaptic plasticity. These findings reveal potential mechanisms for the antidepressant effects of levomilnacipran and offer new insights into the treatments for depression.
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Affiliation(s)
- Yuhan Wu
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China
| | - Zhanpeng Zhu
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China
| | - Tian Lan
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China
| | - Shuhan Li
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China
| | - Ye Li
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China
| | - Changmin Wang
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China
| | - Yabo Feng
- Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, 250021, People's Republic of China
| | - Xueqin Mao
- Department of Psychology, Qilu Hospital of Shandong University, 107 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China.
| | - Shuyan Yu
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China.
- Shandong Provincial Key Laboratory of Mental Disorders, School of Basic Medical Sciences, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China.
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Tsuneki H, Honda K, Sekine Y, Yahata K, Yasue M, Fujishima M, Takeda R, Wada T, Sasaoka T. C-terminal peptide of preproorexin enhances brain-derived neurotrophic factor expression in rat cerebrocortical cells and recognition memory in mice. Eur J Pharmacol 2024; 964:176306. [PMID: 38145647 DOI: 10.1016/j.ejphar.2023.176306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 12/08/2023] [Accepted: 12/21/2023] [Indexed: 12/27/2023]
Abstract
During the production of orexin A and B from preproorexin, a common precursor protein, in hypothalamic orexin neurons, C-terminal peptide (herein called preproorexin C-peptide) is concomitantly produced via post-translational processing. The predicted three-dimensional structure of preproorexin C-peptide is similar among mammalian species, suggestive of a conserved function in the mammalian brain. However, C-peptide has long been regarded as a non-functional peptide. We herein examined the effects of rat and/or mouse preproorexin C-peptide on gene expression and cell viability in cultured rat cerebrocortical cells and on memory behavior in C57BL/6J mice. Rat and mouse C-peptides both increased brain-derived neurotrophic factor (Bdnf) mRNA levels. Moreover, C-peptide enhanced high K+-, glutamate-, and BDNF-induced increases in Bdnf mRNA levels without affecting forskolin-induced Bdnf expression. H-89, a protein kinase A inhibitor, blocked C-peptide-induced Bdnf expression, whereas rolipram, a phosphodiesterase inhibitor, enhanced this effect. Intracellular cyclic AMP concentrations were elevated by C-peptide. These results demonstrate that preproorexin C-peptide promoted Bdnf mRNA expression by a cyclic AMP-dependent mechanism. Eleven amino acids at the N terminus of rat preproorexin C-peptide exerted similar effects on Bdnf expression as full-length preproorexin C-peptide. Preproorexin C-peptide also exerted protective effects against CoCl2-induced neuronal cell death. An intracerebroventricular injection of mouse preproorexin C-peptide induced c-fos and Bdnf expression in the cerebral cortex and hippocampus and enhanced novel object recognition memory in mice. Collectively, the present results show that preproorexin C-peptide is a functional substance, at least in some pharmacological and neuronal settings.
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Affiliation(s)
- Hiroshi Tsuneki
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan; Department of Integrative Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
| | - Kosuke Honda
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Yurika Sekine
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Koji Yahata
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Moeka Yasue
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Masashi Fujishima
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Ryuta Takeda
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Tsutomu Wada
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Toshiyasu Sasaoka
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
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9
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Cefis M, Chaney R, Wirtz J, Méloux A, Quirié A, Leger C, Prigent-Tessier A, Garnier P. Molecular mechanisms underlying physical exercise-induced brain BDNF overproduction. Front Mol Neurosci 2023; 16:1275924. [PMID: 37868812 PMCID: PMC10585026 DOI: 10.3389/fnmol.2023.1275924] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 09/18/2023] [Indexed: 10/24/2023] Open
Abstract
Accumulating evidence supports that physical exercise (EX) is the most effective non-pharmacological strategy to improve brain health. EX prevents cognitive decline associated with age and decreases the risk of developing neurodegenerative diseases and psychiatric disorders. These positive effects of EX can be attributed to an increase in neurogenesis and neuroplastic processes, leading to learning and memory improvement. At the molecular level, there is a solid consensus to involve the neurotrophin brain-derived neurotrophic factor (BDNF) as the crucial molecule for positive EX effects on the brain. However, even though EX incontestably leads to beneficial processes through BDNF expression, cellular sources and molecular mechanisms underlying EX-induced cerebral BDNF overproduction are still being elucidated. In this context, the present review offers a summary of the different molecular mechanisms involved in brain's response to EX, with a specific focus on BDNF. It aims to provide a cohesive overview of the three main mechanisms leading to EX-induced brain BDNF production: the neuronal-dependent overexpression, the elevation of cerebral blood flow (hemodynamic hypothesis), and the exerkine signaling emanating from peripheral tissues (humoral response). By shedding light on these intricate pathways, this review seeks to contribute to the ongoing elucidation of the relationship between EX and cerebral BDNF expression, offering valuable insights into the potential therapeutic implications for brain health enhancement.
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Affiliation(s)
- Marina Cefis
- Département des Sciences de l’Activité Physique, Faculté des Sciences, Université du Québec à Montréal, Montreal, QC, Canada
- INSERM UMR1093-CAPS, Université de Bourgogne, UFR des Sciences de Santé, Dijon, France
| | - Remi Chaney
- INSERM UMR1093-CAPS, Université de Bourgogne, UFR des Sciences de Santé, Dijon, France
| | - Julien Wirtz
- INSERM UMR1093-CAPS, Université de Bourgogne, UFR des Sciences de Santé, Dijon, France
| | - Alexandre Méloux
- INSERM UMR1093-CAPS, Université de Bourgogne, UFR des Sciences de Santé, Dijon, France
| | - Aurore Quirié
- INSERM UMR1093-CAPS, Université de Bourgogne, UFR des Sciences de Santé, Dijon, France
| | - Clémence Leger
- INSERM UMR1093-CAPS, Université de Bourgogne, UFR des Sciences de Santé, Dijon, France
| | - Anne Prigent-Tessier
- INSERM UMR1093-CAPS, Université de Bourgogne, UFR des Sciences de Santé, Dijon, France
| | - Philippe Garnier
- INSERM UMR1093-CAPS, Université de Bourgogne, UFR des Sciences de Santé, Dijon, France
- Département Génie Biologique, Institut Universitaire de Technologie, Dijon, France
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10
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Zosen D, Kondratskaya E, Kaplan-Arabaci O, Haugen F, Paulsen RE. Antidepressants escitalopram and venlafaxine up-regulate BDNF promoter IV but down-regulate neurite outgrowth in differentiating SH-SY5Y neurons. Neurochem Int 2023; 169:105571. [PMID: 37451345 DOI: 10.1016/j.neuint.2023.105571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 06/26/2023] [Accepted: 07/04/2023] [Indexed: 07/18/2023]
Abstract
Antidepressants are used to treat depression and some anxiety disorders, including use in pregnant patients. The pharmacological actions of these drugs generally determine the uptake and metabolism of a series of neurotransmitters, such as serotonin, norepinephrine, or dopamine, along with an increase in BDNF expression. However, many aspects of antidepressant action remain unknown, particularly whether antidepressants interfere with normal neurodevelopment when taken by pregnant women. In order to reveal cellular and molecular implications crucial to the functioning of pathways related to antidepressant effects, we performed an investigation on neuronally differentiating human SH-SY5Y cells. To our knowledge, this is the first time human SH-SY5Y cells in cultures of purely neuronal cells induced by controlled differentiation with retinoic acid are followed by short-term 48-h exposure to 0.1-10 μM escitalopram or venlafaxine. Treatment with antidepressants (1 μM) did not affect the electrophysiological properties of SH-SY5Y cells. However, the percentage of mature neurons exhibiting voltage-gated sodium currents was substantially higher in cultures pre-treated with either antidepressant. After exposure to escitalopram or venlafaxine, we observed a concentration-dependent increase in activity-dependent BDNF promoter IV activation. The assessment of neurite metrics showed significant down-regulation of neurite outgrowth upon exposure to venlafaxine. Identified changes may represent links to molecular processes of importance to depression and be involved in neurodevelopmental alterations observed in postpartum children exposed to antidepressants antenatally.
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Affiliation(s)
- Denis Zosen
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway
| | - Elena Kondratskaya
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; NORMENT, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
| | - Oykum Kaplan-Arabaci
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway
| | - Fred Haugen
- Department of Work Psychology and Physiology, National Institute of Occupational Health (STAMI), Oslo, Norway
| | - Ragnhild Elisabeth Paulsen
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
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11
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Costa GA, de Gusmão Taveiros Silva NK, Marianno P, Chivers P, Bailey A, Camarini R. Environmental Enrichment Increased Bdnf Transcripts in the Prefrontal Cortex: Implications for an Epigenetically Controlled Mechanism. Neuroscience 2023; 526:277-289. [PMID: 37419403 DOI: 10.1016/j.neuroscience.2023.07.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 06/26/2023] [Accepted: 07/01/2023] [Indexed: 07/09/2023]
Abstract
Environmental enrichment (EE) is a condition characterized by its complexity regarding social contact, exposure to novelty, tactile stimuli and voluntary exercise, also is considered as a eustress model. The impact of EE on brain physiology and behavioral outcomes may be at least partly underpinned by mechanisms involving the modulation of the brain-derived neurotrophic factor (BDNF), but the connection between specific Bdnf exon expression and their epigenetic regulation remain poorly understood. This study aimed to dissect the transcriptional and epigenetic regulatory effect of 54-day exposure to EE on BDNF by analysing individual BDNF exons mRNA expression and the DNA methylation profile of a key transcriptional regulator of the Bdnf gene, exon IV, in the prefrontal cortex (PFC) of C57BL/6 male mice (sample size = 33). Bdnf exons II, IV, VI and IX mRNA expression were upregulated and methylation levels at two CpG sites of exon IV were reduced in the PFC of EE mice. As deficit in exon IV expression has also been causally implicated in stress-related psychopathologies, we also assessed anxiety-like behavior and plasma corticosterone levels in these mice to determine any potential correlation. However, no changes were observed in EE mice. The findings may suggest an EE-induced epigenetic control of BDNF exon expression via a mechanism involving exon IV methylation. The findings of this study contribute to the current literature by dissecting the Bdnf gene topology in the PFC where transcriptional and epigenetic regulatory effect of EE takes place.
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Affiliation(s)
- Gabriel Araújo Costa
- Pharmacology Department, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | | | - Priscila Marianno
- Pharmacology Department, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Priti Chivers
- School of Biosciences & Medicine, Faculty of Health & Medical Sciences, University of Surrey, Guildford, UK
| | - Alexis Bailey
- Pharmacology Section, Institute of Medical and Biomedical Education, St George's University of London, London, UK.
| | - Rosana Camarini
- Pharmacology Department, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
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12
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Arévalo JC, Deogracias R. Mechanisms Controlling the Expression and Secretion of BDNF. Biomolecules 2023; 13:biom13050789. [PMID: 37238659 DOI: 10.3390/biom13050789] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/19/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023] Open
Abstract
Brain-derived nerve factor (BDNF), through TrkB receptor activation, is an important modulator for many different physiological and pathological functions in the nervous system. Among them, BDNF plays a crucial role in the development and correct maintenance of brain circuits and synaptic plasticity as well as in neurodegenerative diseases. The proper functioning of the central nervous system depends on the available BDNF concentrations, which are tightly regulated at transcriptional and translational levels but also by its regulated secretion. In this review we summarize the new advances regarding the molecular players involved in BDNF release. In addition, we will address how changes of their levels or function in these proteins have a great impact in those functions modulated by BDNF under physiological and pathological conditions.
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Affiliation(s)
- Juan Carlos Arévalo
- Department of Cell Biology and Pathology, Institute of Neurosciences of Castille and Leon (INCyL), University of Salamanca, 37007 Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Rubén Deogracias
- Department of Cell Biology and Pathology, Institute of Neurosciences of Castille and Leon (INCyL), University of Salamanca, 37007 Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
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13
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You H, Lu B. Diverse Functions of Multiple Bdnf Transcripts Driven by Distinct Bdnf Promoters. Biomolecules 2023; 13:655. [PMID: 37189402 PMCID: PMC10135494 DOI: 10.3390/biom13040655] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 04/01/2023] [Accepted: 04/04/2023] [Indexed: 05/17/2023] Open
Abstract
The gene encoding brain-derived neurotrophic factor (Bdnf) consists of nine non-coding exons driven by unique promoters, leading to the expression of nine Bdnf transcripts that play different roles in various brain regions and physiological stages. In this manuscript, we present a comprehensive overview of the molecular regulation and structural characteristics of the multiple Bdnf promoters, along with a summary of the current knowledge on the cellular and physiological functions of the distinct Bdnf transcripts produced by these promoters. Specifically, we summarized the role of Bdnf transcripts in psychiatric disorders, including schizophrenia and anxiety, as well as the cognitive functions associated with specific Bdnf promoters. Moreover, we examine the involvement of different Bdnf promoters in various aspects of metabolism. Finally, we propose future research directions that will enhance our understanding of the complex functions of Bdnf and its diverse promoters.
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Affiliation(s)
- He You
- School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China;
- School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Bai Lu
- School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China;
- Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Centre, 10 Marais Street, Stellenbosch 7600, South Africa
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14
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Liao GY, Xu H, Shumate J, Scampavia L, Spicer T, Xu B. High throughput assay for compounds that boost BDNF expression in neurons. SLAS DISCOVERY : ADVANCING LIFE SCIENCES R & D 2023; 28:88-94. [PMID: 36842668 PMCID: PMC10759152 DOI: 10.1016/j.slasd.2023.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/30/2023] [Accepted: 02/21/2023] [Indexed: 02/27/2023]
Abstract
Deficiencies in brain-derived neurotrophic factor (BDNF) have been linked to several brain disorders, making compounds that can boost neuronal BDNF synthesis attractive as potential therapeutics. However, a sensitive and quantitative BDNF assay for high-throughput screening (HTS) is still missing. Here we report the generation of a new mouse Bdnf allele, BdnfNLuc, in which the sequence encoding nano luciferase (NLuc) is inserted into the Bdnf locus immediately before the stop codon so that the allele will produce a BDNF-NLuc fusion protein. BDNF-NLuc protein appears to function like BDNF as BdnfNLuc/NLuc homozygous mice grew and behaved almost normally. We were able to establish and optimize cultures of cortical and hippocampal BdnfNLuc/+ neurons isolated from mouse embryos in 384-well plates. We used the cultures as a phenotypic assay to detect the ability of 10 mM KCl to stimulate BDNF synthesis and achieved a reproducible Z' factor > 0.50 for the assay, a measure considered suitable for HTS. We successfully scaled up the assay to screen the 1280-compound LOPAC library (Library of Pharmacologically Active Compounds). The screen identified several BDNF-boosting compounds, one of which is Bay K8644, a L-type voltage-gated calcium channel (L-VGCC) agonist, which was previously shown to stimulate BDNF synthesis. These results indicate that our phenotypic neuronal assay is ready for HTS to identify novel BDNF-boosting compounds.
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Affiliation(s)
- Guey-Ying Liao
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Haifei Xu
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Justin Shumate
- Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Louis Scampavia
- Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Timothy Spicer
- Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Baoji Xu
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, 130 Scripps Way, Jupiter, FL 33458, USA.
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15
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Sadashivaiah V, Tippani M, Page SC, Kwon SH, Bach SV, Bharadwaj RA, Hyde TM, Kleinman JE, Jaffe AE, Maynard KR. SUFI: an automated approach to spectral unmixing of fluorescent multiplex images captured in mouse and post-mortem human brain tissues. BMC Neurosci 2023; 24:6. [PMID: 36698068 PMCID: PMC9878864 DOI: 10.1186/s12868-022-00765-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 12/06/2022] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Multispectral fluorescence imaging coupled with linear unmixing is a form of image data collection and analysis that allows for measuring multiple molecular signals in a single biological sample. Multiple fluorescent dyes, each measuring a unique molecule, are simultaneously measured and subsequently "unmixed" to provide a read-out for each molecular signal. This strategy allows for measuring highly multiplexed signals in a single data capture session, such as multiple proteins or RNAs in tissue slices or cultured cells, but can often result in mixed signals and bleed-through problems across dyes. Existing spectral unmixing algorithms are not optimized for challenging biological specimens such as post-mortem human brain tissue, and often require manual intervention to extract spectral signatures. We therefore developed an intuitive, automated, and flexible package called SUFI: spectral unmixing of fluorescent images. RESULTS This package unmixes multispectral fluorescence images by automating the extraction of spectral signatures using vertex component analysis, and then performs one of three unmixing algorithms derived from remote sensing. We evaluate these remote sensing algorithms' performances on four unique biological datasets and compare the results to unmixing results obtained using ZEN Black software (Zeiss). We lastly integrate our unmixing pipeline into the computational tool dotdotdot, which is used to quantify individual RNA transcripts at single cell resolution in intact tissues and perform differential expression analysis, and thereby provide an end-to-end solution for multispectral fluorescence image analysis and quantification. CONCLUSIONS In summary, we provide a robust, automated pipeline to assist biologists with improved spectral unmixing of multispectral fluorescence images.
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Affiliation(s)
- Vijay Sadashivaiah
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, 21205, USA.
| | - Madhavi Tippani
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, 21205, USA
| | - Stephanie C Page
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, 21205, USA
| | - Sang Ho Kwon
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, 21205, USA
| | - Svitlana V Bach
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, 21205, USA
| | - Rahul A Bharadwaj
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, 21205, USA
| | - Thomas M Hyde
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, 21205, USA
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
- Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - Joel E Kleinman
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, 21205, USA
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - Andrew E Jaffe
- Department of Genetic Medicine, McKusick-Nathans Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
- Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
| | - Kristen R Maynard
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, 21205, USA.
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16
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Differential Regulation of the BDNF Gene in Cortical and Hippocampal Neurons. J Neurosci 2022; 42:9110-9128. [PMID: 36316156 PMCID: PMC9761680 DOI: 10.1523/jneurosci.2535-21.2022] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 09/18/2022] [Accepted: 10/19/2022] [Indexed: 11/05/2022] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is a widely expressed neurotrophin that supports the survival, differentiation, and signaling of various neuronal populations. Although it has been well described that expression of BDNF is strongly regulated by neuronal activity, little is known whether regulation of BDNF expression is similar in different brain regions. Here, we focused on this fundamental question using neuronal populations obtained from rat cerebral cortices and hippocampi of both sexes. First, we thoroughly characterized the role of the best-described regulators of BDNF gene - cAMP response element binding protein (CREB) family transcription factors, and show that activity-dependent BDNF expression depends more on CREB and the coactivators CREB binding protein (CBP) and CREB-regulated transcriptional coactivator 1 (CRTC1) in cortical than in hippocampal neurons. Our data also reveal an important role of CREB in the early induction of BDNF mRNA expression after neuronal activity and only modest contribution after prolonged neuronal activity. We further corroborated our findings at BDNF protein level. To determine the transcription factors regulating BDNF expression in these rat brain regions in addition to CREB family, we used in vitro DNA pulldown assay coupled with mass spectrometry, chromatin immunoprecipitation (ChIP), and bioinformatics, and propose a number of neurodevelopmentally important transcription factors, such as FOXP1, SATB2, RAI1, BCL11A, and TCF4 as brain region-specific regulators of BDNF expression. Together, our data reveal complicated brain region-specific fine-tuning of BDNF expression.SIGNIFICANCE STATEMENT To date, majority of the research has focused on the regulation of brain-derived neurotrophic factor (BDNF) in the brain but much less is known whether the regulation of BDNF expression is universal in different brain regions and neuronal populations. Here, we report that the best described regulators of BDNF gene from the cAMP-response element binding protein (CREB) transcription factor family have a more profound role in the activity-dependent regulation of BDNF in cortex than in hippocampus. Our results indicate a brain region-specific fine tuning of BDNF expression. Moreover, we have used unbiased determination of novel regulators of the BDNF gene and report a number of neurodevelopmentally important transcription factors as novel potential regulators of the BDNF expression.
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17
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Łuczkowska K, Kulig P, Baumert B, Machaliński B. Brain-derived neurotrophic factor: focus on the pathogenesis of multiple myeloma and the development of treatment-induced peripheral neuropathy. Leuk Lymphoma 2022; 63:3044-3051. [PMID: 35999712 DOI: 10.1080/10428194.2022.2113535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
For many years, intensive research has been carried out on the in-depth understanding of the pathogenesis of multiple myeloma (MM). Nevertheless, the multifactorial nature of the disease, the development of drug resistance, and the side effects of therapy, make it difficult to effectively treat patients. One of the many factors involved in the pathogenesis of MM is brain-derived neurotrophic factor (BDNF). This factor is widely described as a neuroregenerative and neuroprotective agent, but it also regulates non-neuronal cell functions, such as proliferation, apoptosis, and viability. Therefore, BDNF appears to be a good therapeutic target in MM. On the other hand, its decreased concentration during treatment closely correlates with the development of peripheral neuropathy (PN). BDNF dualism requires a detailed understanding of its action on individual molecular mechanisms. Perhaps the optimization of the BDNF level will contribute to the improvement of MM treatment and the reduction of chemotherapy side effects.
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Affiliation(s)
- Karolina Łuczkowska
- Department of General Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Piotr Kulig
- Department of General Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Bartłomiej Baumert
- Department of Bone Marrow Transplantation, Pomeranian Medical University, Szczecin, Poland
| | - Bogusław Machaliński
- Department of General Pathology, Pomeranian Medical University, Szczecin, Poland.,Department of Bone Marrow Transplantation, Pomeranian Medical University, Szczecin, Poland
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18
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Tippani M, Pattie EA, Davis BA, Nguyen CV, Wang Y, Sripathy SR, Maher BJ, Martinowich K, Jaffe AE, Page SC. CaPTure: Calcium PeakToolbox for analysis of in vitro calcium imaging data. BMC Neurosci 2022; 23:71. [PMID: 36451089 PMCID: PMC9710137 DOI: 10.1186/s12868-022-00751-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/02/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Calcium imaging is a powerful technique for recording cellular activity across large populations of neurons. However, analysis methods capable of single-cell resolution in cultured neurons, especially for cultures derived from human induced pluripotent stem cells (hiPSCs), are lacking. Existing methods lack scalability to accommodate high-throughput comparisons between multiple lines, across developmental timepoints, or across pharmacological manipulations. RESULTS To address this need we developed CaPTure, a scalable, automated Ca2+ imaging analysis pipeline ( https://github.com/LieberInstitute/CaPTure ). CaPTuredetects neurons, classifies and quantifies spontaneous activity, quantifies synchrony metrics, and generates cell- and network-specific metrics that facilitate phenotypic discovery. The method is compatible with parallel processing on computing clusters without requiring significant user input or parameter modification. CONCLUSION CaPTure allows for rapid assessment of neuronal activity in cultured cells at cellular resolution, rendering it amenable to high-throughput screening and phenotypic discovery. The platform can be applied to both human- and rodent-derived neurons and is compatible with many imaging systems.
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Affiliation(s)
- Madhavi Tippani
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA
| | - Elizabeth A Pattie
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA
| | - Brittany A Davis
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA
| | - Claudia V Nguyen
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA
| | - Yanhong Wang
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA
| | - Srinidhi Rao Sripathy
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA
| | - Brady J Maher
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
- Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - Keri Martinowich
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
- Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - Andrew E Jaffe
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA
- Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
- McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
| | - Stephanie Cerceo Page
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA.
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19
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Rentería I, García-Suárez PC, Fry AC, Moncada-Jiménez J, Machado-Parra JP, Antunes BM, Jiménez-Maldonado A. The Molecular Effects of BDNF Synthesis on Skeletal Muscle: A Mini-Review. Front Physiol 2022; 13:934714. [PMID: 35874524 PMCID: PMC9306488 DOI: 10.3389/fphys.2022.934714] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 06/14/2022] [Indexed: 11/13/2022] Open
Abstract
The brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family which is generated mainly by the brain. Its main role involve synaptic modulation, neurogenesis, neuron survival, immune regulation, myocardial contraction, and angiogenesis in the brain. Together with the encephalon, some peripheral tissues synthesize BDNF like skeletal muscle. On this tissue, this neurotrophin participates on cellular mechanisms related to muscle function maintenance and plasticity as reported on recent scientific works. Moreover, during exercise stimuli the BDNF contributes directly to strengthening neuromuscular junctions, muscle regeneration, insulin-regulated glucose uptake and β-oxidation processes in muscle tissue. Given its vital relevance on many physiological mechanisms, the current mini-review focuses on discussing up-to-date knowledge about BDNF production in skeletal muscle and how this neurotrophin impacts skeletal muscle biology.
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Affiliation(s)
- I Rentería
- Facultad de Deportes, Universidad Autónoma de Baja California, Ensenada, Mexico
| | - P C García-Suárez
- Facultad de Deportes, Universidad Autónoma de Baja California, Ensenada, Mexico.,Department of Health, Sports and Exercise Sciences, University of Kansas, Lawrence, KS, United States
| | - A C Fry
- Department of Health, Sports and Exercise Sciences, University of Kansas, Lawrence, KS, United States
| | - J Moncada-Jiménez
- Human Movement Sciences Research Center (CIMOHU), University of Costa Rica, San José, Costa Rica
| | - J P Machado-Parra
- Facultad de Deportes, Universidad Autónoma de Baja California, Ensenada, Mexico
| | - B M Antunes
- Facultad de Deportes, Universidad Autónoma de Baja California, Ensenada, Mexico
| | - A Jiménez-Maldonado
- Facultad de Deportes, Universidad Autónoma de Baja California, Ensenada, Mexico
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20
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Tremblay MW, Green MV, Goldstein BM, Aldridge AI, Rosenfeld JA, Streff H, Tan WD, Craigen W, Bekheirnia N, Al Tala S, West AE, Jiang YH. Mutations of the histone linker H1-4 in neurodevelopmental disorders and functional characterization of neurons expressing C-terminus frameshift mutant H1.4. Hum Mol Genet 2022; 31:1430-1442. [PMID: 34788807 PMCID: PMC9271223 DOI: 10.1093/hmg/ddab321] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/18/2021] [Accepted: 10/26/2021] [Indexed: 12/29/2022] Open
Abstract
Rahman syndrome (RMNS) is a rare genetic disorder characterized by mild to severe intellectual disability, hypotonia, anxiety, autism spectrum disorder, vision problems, bone abnormalities and dysmorphic facies. RMNS is caused by de novo heterozygous mutations in the histone linker gene H1-4; however, mechanisms underlying impaired neurodevelopment in RMNS are not understood. All reported mutations associated with RMNS in H1-4 are small insertions or deletions that create a shared frameshift, resulting in a H1.4 protein that is both truncated and possessing an abnormal C-terminus frameshifted tail (H1.4 CFT). To expand understanding of mutations and phenotypes associated with mutant H1-4, we identified new variants at both the C- and N-terminus of H1.4. The clinical features of mutations identified at the C-terminus are consistent with other reports and strengthen the support of pathogenicity of H1.4 CFT. To understand how H1.4 CFT may disrupt brain function, we exogenously expressed wild-type or H1.4 CFT protein in rat hippocampal neurons and assessed neuronal structure and function. Genome-wide transcriptome analysis revealed ~ 400 genes altered in the presence of H1.4 CFT. Neuronal genes downregulated by H1.4 CFT were enriched for functional categories involved in synaptic communication and neuropeptide signaling. Neurons expressing H1.4 CFT also showed reduced neuronal activity on multielectrode arrays. These data are the first to characterize the transcriptional and functional consequence of H1.4 CFT in neurons. Our data provide insight into causes of neurodevelopmental impairments associated with frameshift mutations in the C-terminus of H1.4 and highlight the need for future studies on the function of histone H1.4 in neurons.
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Affiliation(s)
- Martine W Tremblay
- University Program in Genetics and Genomics, Duke University, Durham NC 27710, USA
- Department of Neurobiology, Duke University, Durham NC 27710, USA
| | - Matthew V Green
- Department of Neurobiology, Duke University, Durham NC 27710, USA
| | | | - Andrew I Aldridge
- University Program in Genetics and Genomics, Duke University, Durham NC 27710, USA
- Department of Neurobiology, Duke University, Durham NC 27710, USA
| | - Jill A Rosenfeld
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX 77030, USA
- Baylor Genetics Laboratories, Baylor College of Medicine, Houston TX 77030, USA
| | - Haley Streff
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX 77030, USA
| | - Wendy D Tan
- Department of Neurobiology, Duke University, Durham NC 27710, USA
| | - William Craigen
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX 77030, USA
| | - Nasim Bekheirnia
- Department of Pediatrics, Renal section, Baylor College of Medicine, Houston TX 77030, USA
| | - Saeed Al Tala
- Department of Pediatrics, Armed Forces Hospital SR, Khamis Mushayt 61961, Saudi Arabia
| | - Anne E West
- University Program in Genetics and Genomics, Duke University, Durham NC 27710, USA
- Department of Neurobiology, Duke University, Durham NC 27710, USA
| | - Yong-hui Jiang
- Department of Genetics, Yale University School of Medicine, New Haven CT 06520, USA
- Neuroscience, Yale University School of Medicine, New Haven CT 06520, USA
- Pediatrics, Yale University School of Medicine, New Haven CT 06520, USA
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21
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Zhao XP, Li H, Dai RP. Neuroimmune crosstalk through brain-derived neurotrophic factor and its precursor pro-BDNF: New insights into mood disorders. World J Psychiatry 2022; 12:379-392. [PMID: 35433323 PMCID: PMC8968497 DOI: 10.5498/wjp.v12.i3.379] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 08/22/2021] [Accepted: 01/23/2022] [Indexed: 02/06/2023] Open
Abstract
Mood disorders are the most common mental disorders, affecting approximately 350 million people globally. Recent studies have shown that neuroimmune interaction regulates mood disorders. Brain-derived neurotrophic factor (BDNF) and its precursor pro-BDNF, are involved in the neuroimmune crosstalk during the development of mood disorders. BDNF is implicated in the pathophysiology of psychiatric and neurological disorders especially in antidepressant pharmacotherapy. In this review, we describe the functions of BDNF/pro-BDNF signaling in the central nervous system in the context of mood disorders. In addition, we summarize the developments for BDNF and pro-BDNF functions in mood disorders. This review aims to provide new insights into the impact of neuroimmune interaction on mood disorders and reveal a new basis for further development of diagnostic targets and mood disorders.
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Affiliation(s)
- Xiao-Pei Zhao
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Hui Li
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Ru-Ping Dai
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
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22
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Zheng N, Fitzpatrick V, Cheng R, Shi L, Kaplan DL, Yang C. Photoacoustic Carbon Nanotubes Embedded Silk Scaffolds for Neural Stimulation and Regeneration. ACS NANO 2022; 16:2292-2305. [PMID: 35098714 DOI: 10.1021/acsnano.1c08491] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/19/2023]
Abstract
Neural interfaces using biocompatible scaffolds provide crucial properties, such as cell adhesion, structural support, and mass transport, for the functional repair of nerve injuries and neurodegenerative diseases. Neural stimulation has also been found to be effective in promoting neural regeneration. This work provides a generalized strategy to integrate photoacoustic (PA) neural stimulation into hydrogel scaffolds using a nanocomposite hydrogel approach. Specifically, polyethylene glycol (PEG)-functionalized carbon nanotubes (CNT), highly efficient photoacoustic agents, are embedded into silk fibroin to form biocompatible and soft photoacoustic materials. We show that these photoacoustic functional scaffolds enable nongenetic activation of neurons with a spatial precision defined by the area of light illumination, promoting neuron regeneration. These CNT/silk scaffolds offered reliable and repeatable photoacoustic neural stimulation, and 94% of photoacoustic-stimulated neurons exhibit a fluorescence change larger than 10% in calcium imaging in the light-illuminated area. The on-demand photoacoustic stimulation increased neurite outgrowth by 1.74-fold in a rat dorsal root ganglion model, when compared to the unstimulated group. We also confirmed that promoted neurite outgrowth by photoacoustic stimulation is associated with an increased concentration of neurotrophic factor (BDNF). As a multifunctional neural scaffold, CNT/silk scaffolds demonstrated nongenetic PA neural stimulation functions and promoted neurite outgrowth, providing an additional method for nonpharmacological neural regeneration.
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Affiliation(s)
| | - Vincent Fitzpatrick
- Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States
| | | | | | - David L Kaplan
- Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States
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23
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Gao L, Zhang Y, Sterling K, Song W. Brain-derived neurotrophic factor in Alzheimer's disease and its pharmaceutical potential. Transl Neurodegener 2022; 11:4. [PMID: 35090576 PMCID: PMC8796548 DOI: 10.1186/s40035-022-00279-0] [Citation(s) in RCA: 236] [Impact Index Per Article: 78.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 01/01/2022] [Indexed: 12/14/2022] Open
Abstract
Synaptic abnormalities are a cardinal feature of Alzheimer's disease (AD) that are known to arise as the disease progresses. A growing body of evidence suggests that pathological alterations to neuronal circuits and synapses may provide a mechanistic link between amyloid β (Aβ) and tau pathology and thus may serve as an obligatory relay of the cognitive impairment in AD. Brain-derived neurotrophic factors (BDNFs) play an important role in maintaining synaptic plasticity in learning and memory. Considering AD as a synaptic disorder, BDNF has attracted increasing attention as a potential diagnostic biomarker and a therapeutical molecule for AD. Although depletion of BDNF has been linked with Aβ accumulation, tau phosphorylation, neuroinflammation and neuronal apoptosis, the exact mechanisms underlying the effect of impaired BDNF signaling on AD are still unknown. Here, we present an overview of how BDNF genomic structure is connected to factors that regulate BDNF signaling. We then discuss the role of BDNF in AD and the potential of BDNF-targeting therapeutics for AD.
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Affiliation(s)
- Lina Gao
- Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Institute of Mental Health, College of Pharmacy, Jining Medical University, Jining, 272067, Shandong, China
- Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Yun Zhang
- National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Keenan Sterling
- Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Weihong Song
- Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Institute of Mental Health, College of Pharmacy, Jining Medical University, Jining, 272067, Shandong, China.
- Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
- National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, 325001, Zhejiang, China.
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24
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Miyasaka Y, Yamamoto N. Neuronal Activity Patterns Regulate Brain-Derived Neurotrophic Factor Expression in Cortical Cells via Neuronal Circuits. Front Neurosci 2021; 15:699583. [PMID: 34955705 PMCID: PMC8702648 DOI: 10.3389/fnins.2021.699583] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 11/08/2021] [Indexed: 11/22/2022] Open
Abstract
During development, cortical circuits are remodeled by spontaneous and sensory-evoked activity via alteration of the expression of wiring molecules. An intriguing question is how physiological neuronal activity modifies the expression of these molecules in developing cortical networks. Here, we addressed this issue, focusing on brain-derived neurotrophic factor (BDNF), one of the factors underlying cortical wiring. Real-time imaging of BDNF promoter activity in organotypic slice cultures revealed that patterned stimuli differentially regulated the increase and the time course of the promoter activity in upper layer neurons. Calcium imaging further demonstrated that stimulus-dependent increases in the promoter activity were roughly proportional to the increase in intracellular Ca2+ concentration per unit time. Finally, optogenetic stimulation showed that the promoter activity was increased efficiently by patterned stimulation in defined cortical circuits. These results suggest that physiological stimulation patterns differentially tune activity-dependent gene expression in developing cortical neurons via cortical circuits, synaptic responses, and alteration of intracellular calcium signaling.
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Affiliation(s)
- Yumi Miyasaka
- Laboratory of Cellular and Molecular Neurobiology, Graduate School of Frontier Biosciences, Osaka University, Suita, Japan
| | - Nobuhiko Yamamoto
- Laboratory of Cellular and Molecular Neurobiology, Graduate School of Frontier Biosciences, Osaka University, Suita, Japan
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25
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Sun Y, Zhou D, Rahman MR, Zhu J, Ghoneim D, Cox NJ, Beach TG, Wu C, Gamazon ER, Wu L. A transcriptome-wide association study identifies novel blood-based gene biomarker candidates for Alzheimer's disease risk. Hum Mol Genet 2021; 31:289-299. [PMID: 34387340 PMCID: PMC8831284 DOI: 10.1093/hmg/ddab229] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 07/12/2021] [Accepted: 07/23/2021] [Indexed: 11/12/2022] Open
Abstract
Alzheimer's disease (ad) adversely affects the health, quality of life and independence of patients. There is a critical need to identify novel blood gene biomarkers for ad risk assessment. We performed a transcriptome-wide association study to identify biomarker candidates for ad risk. We leveraged two sets of gene expression prediction models of blood developed using different reference panels and modeling strategies. By applying the prediction models to a meta-GWAS including 71 880 (proxy) cases and 383 378 (proxy) controls, we identified significant associations of genetically determined expression of 108 genes in blood with ad risk. Of these, 15 genes were differentially expressed between ad patients and controls with concordant directions in measured expression data. With evidence from the analyses based on both genetic instruments and directly measured expression levels, this study identifies 15 genes with strong support as biomarkers in blood for ad risk, which may enhance ad risk assessment and mechanism-focused studies.
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Affiliation(s)
- Yanfa Sun
- Department of Animal Science and Veterinary Medicine, College of Life Science, Longyan University, Longyan, Fujian, 364012, P.R. China
- Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI 96813, USA
- Fujian Provincial Key Laboratory for the Prevention and Control of Animal Infectious Diseases and Biotechnology, Longyan, Fujian 364012, P.R. China
- Fujian Province Universities Key Laboratory of Preventive Veterinary Medicine and Biotechnology (Longyan University), Longyan, Fujian, 364012, P.R. China
| | - Dan Zhou
- Vanderbilt Genetics Institute and Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Md Rezanur Rahman
- Queensland Brain Institute, The University of Queensland, Brisbane, Qld 4072, Australia
| | - Jingjing Zhu
- Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI 96813, USA
| | - Dalia Ghoneim
- Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI 96813, USA
| | - Nancy J Cox
- Vanderbilt Genetics Institute and Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Thomas G Beach
- Banner Sun Health Research Institute, Sun City, AZ 85351, USA
| | - Chong Wu
- Department of Statistics, Florida State University, Tallahassee, FL 32306, USA
| | - Eric R Gamazon
- Vanderbilt Genetics Institute and Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Clare Hall, University of Cambridge, Cambridge CB3 9AL, UK
- MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SL, UK
| | - Lang Wu
- Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI 96813, USA
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26
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Loss of O-GlcNAcylation on MeCP2 at Threonine 203 Leads to Neurodevelopmental Disorders. Neurosci Bull 2021; 38:113-134. [PMID: 34773221 PMCID: PMC8821740 DOI: 10.1007/s12264-021-00784-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 08/06/2021] [Indexed: 02/03/2023] Open
Abstract
Mutations of the X-linked methyl-CpG-binding protein 2 (MECP2) gene in humans are responsible for most cases of Rett syndrome (RTT), an X-linked progressive neurological disorder. While genome-wide screens in clinical trials have revealed several putative RTT-associated mutations in MECP2, their causal relevance regarding the functional regulation of MeCP2 at the etiologic sites at the protein level requires more evidence. In this study, we demonstrated that MeCP2 was dynamically modified by O-linked-β-N-acetylglucosamine (O-GlcNAc) at threonine 203 (T203), an etiologic site in RTT patients. Disruption of the O-GlcNAcylation of MeCP2 specifically at T203 impaired dendrite development and spine maturation in cultured hippocampal neurons, and disrupted neuronal migration, dendritic spine morphogenesis, and caused dysfunction of synaptic transmission in the developing and juvenile mouse cerebral cortex. Mechanistically, genetic disruption of O-GlcNAcylation at T203 on MeCP2 decreased the neuronal activity-induced induction of Bdnf transcription. Our study highlights the critical role of MeCP2 T203 O-GlcNAcylation in neural development and synaptic transmission potentially via brain-derived neurotrophic factor.
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27
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Chandra Rajan K, Meng Y, Yu Z, Roberts SB, Vengatesen T. Oyster biomineralization under ocean acidification: From genes to shell. GLOBAL CHANGE BIOLOGY 2021; 27:3779-3797. [PMID: 33964098 DOI: 10.1111/gcb.15675] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 04/02/2021] [Indexed: 05/27/2023]
Abstract
Biomineralization is one of the key processes that is notably affected in marine calcifiers such as oysters under ocean acidification (OA). Understanding molecular changes in the biomineralization process under OA and its heritability, therefore, is key to developing conservation strategies for protecting ecologically and economically important oyster species. To do this, in this study, we have explicitly chosen the tissue involved in biomineralization (mantle) of an estuarine commercial oyster species, Crassostrea hongkongensis. The primary aim of this study is to understand the influence of DNA methylation over gene expression of mantle tissue under decreased ~pH 7.4, a proxy of OA, and to extrapolate if these molecular changes can be observed in the product of biomineralization-the shell. We grew early juvenile C. hongkongensis, under decreased ~pH 7.4 and control ~pH 8.0 over 4.5 months and studied OA-induced DNA methylation and gene expression patterns along with shell properties such as microstructure, crystal orientation and hardness. The population of oysters used in this study was found to be moderately resilient to OA at the end of the experiment. The expression of key biomineralization-related genes such as carbonic anhydrase and alkaline phosphatase remained unaffected; thus, the mechanical properties of the shell (shell growth rate, hardness and crystal orientation) were also maintained without any significant difference between control and OA conditions with signs of severe dissolution. In addition, this study makes three major conclusions: (1) higher expression of Ca2+ binding/signalling-related genes in the mantle plays a key role in maintaining biomineralization under OA; (2) DNA methylation changes occur in response to OA; however, these methylation changes do not directly control gene expression; and (3) OA would be more of a 'dissolution problem' rather than a 'biomineralization problem' for resilient species that maintain calcification rate with normal shell growth and mechanical properties.
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Affiliation(s)
- Kanmani Chandra Rajan
- The Swire Institute of Marine Science and School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR
| | - Yuan Meng
- State Key Laboratory of Respiratory Disease, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ziniu Yu
- South China Sea Institute of Oceanology, Guangzhou, China
| | - Steven B Roberts
- School of Aquatic and Fishery Sciences, University of Washington, Seattle, WA, USA
| | - Thiyagarajan Vengatesen
- The Swire Institute of Marine Science and School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR
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28
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Effects of datumetine on hippocampal NMDAR activity. Toxicol Rep 2021; 8:1131-1142. [PMID: 34150523 PMCID: PMC8190477 DOI: 10.1016/j.toxrep.2021.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 03/16/2021] [Accepted: 05/21/2021] [Indexed: 11/20/2022] Open
Abstract
The usage (abuse) of Datura metel is becoming increasingly worrisome among the Nigerian populace especially among the youth considering its side effects such as hallucination. This work was designed to identify the phytochemicals in datura plant that potentially interact with NMDAR as it affects the electrical and memory activities of the brain. Ligand-protein interaction was assessed using autodock vina to identify phytochemicals that can interact with NMDAR. Datumetine was found to have the best interaction fit with NMDAR at both allosteric and orthosteric binding sites. Furthermore, using electrophysiological, behavioural and western blotting techniques, it was observed that the administration of datumetine positively modulates the NMDAR current by prolonging burst duration and interspike interval, induces seizures in C57BL/6 mice. Acute exposure leads to memory deficit on NOR and Y-maze test while immunoblotting results showed increased expression of GluN1 and CamKIIα while pCamKIIα-T286, CREB and BDNF were downregulated. The results showed that the memory deficit seen in datura intoxication is possibly the effects of datumetine on NMDAR.
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29
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Wong Fong Sang IE, Schroer J, Halbhuber L, Warm D, Yang JW, Luhmann HJ, Kilb W, Sinning A. Optogenetically Controlled Activity Pattern Determines Survival Rate of Developing Neocortical Neurons. Int J Mol Sci 2021; 22:6575. [PMID: 34205237 PMCID: PMC8235092 DOI: 10.3390/ijms22126575] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/16/2021] [Accepted: 06/16/2021] [Indexed: 12/29/2022] Open
Abstract
A substantial proportion of neurons undergoes programmed cell death (apoptosis) during early development. This process is attenuated by increased levels of neuronal activity and enhanced by suppression of activity. To uncover whether the mere level of activity or also the temporal structure of electrical activity affects neuronal death rates, we optogenetically controlled spontaneous activity of synaptically-isolated neurons in developing cortical cultures. Our results demonstrate that action potential firing of primary cortical neurons promotes neuronal survival throughout development. Chronic patterned optogenetic stimulation allowed to effectively modulate the firing pattern of single neurons in the absence of synaptic inputs while maintaining stable overall activity levels. Replacing the burst firing pattern with a non-physiological, single pulse pattern significantly increased cell death rates as compared to physiological burst stimulation. Furthermore, physiological burst stimulation led to an elevated peak in intracellular calcium and an increase in the expression level of classical activity-dependent targets but also decreased Bax/BCL-2 expression ratio and reduced caspase 3/7 activity. In summary, these results demonstrate at the single-cell level that the temporal pattern of action potentials is critical for neuronal survival versus cell death fate during cortical development, besides the pro-survival effect of action potential firing per se.
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Affiliation(s)
| | | | | | | | | | | | | | - Anne Sinning
- Institute of Physiology, University Medical Center Mainz, Johannes Gutenberg University, Duesbergweg 6, 55128 Mainz, Germany; (I.E.W.F.S.); (J.S.); (L.H.); (D.W.); (J.-W.Y.); (H.J.L.); (W.K.)
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30
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Bilchak JN, Caron G, Côté MP. Exercise-Induced Plasticity in Signaling Pathways Involved in Motor Recovery after Spinal Cord Injury. Int J Mol Sci 2021; 22:ijms22094858. [PMID: 34064332 PMCID: PMC8124911 DOI: 10.3390/ijms22094858] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 04/28/2021] [Accepted: 04/29/2021] [Indexed: 02/06/2023] Open
Abstract
Spinal cord injury (SCI) leads to numerous chronic and debilitating functional deficits that greatly affect quality of life. While many pharmacological interventions have been explored, the current unsurpassed therapy for most SCI sequalae is exercise. Exercise has an expansive influence on peripheral health and function, and by activating the relevant neural pathways, exercise also ameliorates numerous disorders of the central nervous system (CNS). While the exact mechanisms by which this occurs are still being delineated, major strides have been made in the past decade to understand the molecular underpinnings of this essential treatment. Exercise rapidly and prominently affects dendritic sprouting, synaptic connections, neurotransmitter production and regulation, and ionic homeostasis, with recent literature implicating an exercise-induced increase in neurotrophins as the cornerstone that binds many of these effects together. The field encompasses vast complexity, and as the data accumulate, disentangling these molecular pathways and how they interact will facilitate the optimization of intervention strategies and improve quality of life for individuals affected by SCI. This review describes the known molecular effects of exercise and how they alter the CNS to pacify the injury environment, increase neuronal survival and regeneration, restore normal neural excitability, create new functional circuits, and ultimately improve motor function following SCI.
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Miller KM, Mercado NM, Sortwell CE. Synucleinopathy-associated pathogenesis in Parkinson's disease and the potential for brain-derived neurotrophic factor. NPJ PARKINSONS DISEASE 2021; 7:35. [PMID: 33846345 PMCID: PMC8041900 DOI: 10.1038/s41531-021-00179-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 03/17/2021] [Indexed: 12/12/2022]
Abstract
The lack of disease-modifying treatments for Parkinson’s disease (PD) is in part due to an incomplete understanding of the disease’s etiology. Alpha-synuclein (α-syn) has become a point of focus in PD due to its connection to both familial and idiopathic cases—specifically its localization to Lewy bodies (LBs), a pathological hallmark of PD. Within this review, we will present a comprehensive overview of the data linking synuclein-associated Lewy pathology with intracellular dysfunction. We first present the alterations in neuronal proteins and transcriptome associated with LBs in postmortem human PD tissue. We next compare these findings to those associated with LB-like inclusions initiated by in vitro exposure to α-syn preformed fibrils (PFFs) and highlight the profound and relatively unique reduction of brain-derived neurotrophic factor (BDNF) in this model. Finally, we discuss the multitude of ways in which BDNF offers the potential to exert disease-modifying effects on the basal ganglia. What remains unknown is the potential for BDNF to mitigate inclusion-associated dysfunction within the context of synucleinopathy. Collectively, this review reiterates the merit of using the PFF model as a tool to understand the physiological changes associated with LBs, while highlighting the neuroprotective potential of harnessing endogenous BDNF.
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Affiliation(s)
- Kathryn M Miller
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.,Neuroscience Graduate Program, College of Natural Science, Michigan State University, East Lansing, MI, USA
| | - Natosha M Mercado
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.,Neuroscience Graduate Program, College of Natural Science, Michigan State University, East Lansing, MI, USA
| | - Caryl E Sortwell
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA. .,Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, MI, USA.
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Dumas G, Malesys S, Bourgeron T. Systematic detection of brain protein-coding genes under positive selection during primate evolution and their roles in cognition. Genome Res 2021; 31:484-496. [PMID: 33441416 PMCID: PMC7919455 DOI: 10.1101/gr.262113.120] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 01/06/2021] [Indexed: 12/11/2022]
Abstract
The human brain differs from that of other primates, but the genetic basis of these differences remains unclear. We investigated the evolutionary pressures acting on almost all human protein-coding genes (N = 11,667; 1:1 orthologs in primates) based on their divergence from those of early hominins, such as Neanderthals, and non-human primates. We confirm that genes encoding brain-related proteins are among the most strongly conserved protein-coding genes in the human genome. Combining our evolutionary pressure metrics for the protein-coding genome with recent data sets, we found that this conservation applied to genes functionally associated with the synapse and expressed in brain structures such as the prefrontal cortex and the cerebellum. Conversely, several genes presenting signatures commonly associated with positive selection appear as causing brain diseases or conditions, such as micro/macrocephaly, Joubert syndrome, dyslexia, and autism. Among those, a number of DNA damage response genes associated with microcephaly in humans such as BRCA1, NHEJ1, TOP3A, and RNF168 show strong signs of positive selection and might have played a role in human brain size expansion during primate evolution. We also showed that cerebellum granule neurons express a set of genes also presenting signatures of positive selection and that may have contributed to the emergence of fine motor skills and social cognition in humans. This resource is available online and can be used to estimate evolutionary constraints acting on a set of genes and to explore their relative contributions to human traits.
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Affiliation(s)
- Guillaume Dumas
- Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris 75015, France
- Department of Psychiatry, Université de Montreal, CHU Sainte-Justine Hospital, Montreal H3T 1C5, Quebec, Canada
| | - Simon Malesys
- Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris 75015, France
| | - Thomas Bourgeron
- Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris 75015, France
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Lazary J, Eszlari N, Kriko E, Tozser D, Dome P, Deakin JFW, Juhasz G, Bagdy G. Genetic analyses of the endocannabinoid pathway in association with affective phenotypic variants. Neurosci Lett 2021; 744:135600. [PMID: 33421489 DOI: 10.1016/j.neulet.2020.135600] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 12/22/2020] [Accepted: 12/26/2020] [Indexed: 12/21/2022]
Abstract
BACKGORUND Increasing experimental data confirm the crucial role of the endocannabinoid (eCB) system in the regulation of stress response and emotional processes. Despite of the fact, that genetically determined vulnerability for stress is a widely accepted concept in the pathomechanism of affective disorders, replicable human genetic results with interaction analyses of early life trauma and eCB genes are rare. The aim of this study is to test the associations between genetic variants of the eCB pathway, childhood trauma and affective phenotypes. METHODS We selected 18,897 SNPs in the eCB pathway of a GWAS dataset in two general population cohorts (BP sample N = 837; MN sample N = 988). Association analyses were performed on the anxious and depressive subscales of the Brief Symptom Inventory (BSI-ANX and BSI-DEP, respectively). Childhood trauma was assessed by the Childhood Adversity Questionnaire (CAQ). Association analyses were performed in the R 2.0. statistical program using the SNPassoc package. REULTS Genetic effect was more robust in the BP sample than in the MN sample. The most comprehensive results showed that SNPs in the CACNA1C gene associated with depressive phenotype in interaction with CAQ in both BP (p = 1.2 × 10-4) and MN samples (p = 1.6 × 10-4). Direct association analyses (without interaction) provided significant associations between SNPs in different genesets of the two study populations. SNPs in KCNJ3 and GNB5 genes on the BSI-DEP (p = 6.1 × 10-5; p = 7.1 × 10-4) and GNG12 gene on the BSI-ANX (p = 7.4 × 10-6) in the BP sample, while GABAergic, ADCY1 and HTR2A gene variants can be outlined from results of MN sample with less strong p-values. CONCLUSION Our results confirmed the prominent role of CACNA1C gene in the pathogenic effect of early life stress in the development of affective vulnerability in two different study populations using GxE interaction analysis. CACNA1C gene, as it encodes for L-type voltage-gated calcium channel, contributes to neuronal excitability, plasticity and neurogenesis being a crucial effector of both eCB signaling and the BDNF-CREB pathway as well. Our findings suggest that childhood trauma related depression may have more robust genetically determined basis than without early life stress.
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Affiliation(s)
- Judit Lazary
- National Institute of Psychiatry and Addictions, Budapest, Hungary; Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary.
| | - Nora Eszlari
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
| | - Eszter Kriko
- Centre for Bioinformatics, University of Veterinary Medicine Budapest, Hungary
| | - Dora Tozser
- Centre for Bioinformatics, University of Veterinary Medicine Budapest, Hungary
| | - Peter Dome
- Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary
| | - J F William Deakin
- Neuroscience and Psychiatry Unit, University of Manchester, Manchester, United Kingdom
| | - Gabriella Juhasz
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
| | - Gyorgy Bagdy
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
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Gòdia M, Reverter A, González-Prendes R, Ramayo-Caldas Y, Castelló A, Rodríguez-Gil JE, Sánchez A, Clop A. A systems biology framework integrating GWAS and RNA-seq to shed light on the molecular basis of sperm quality in swine. Genet Sel Evol 2020; 52:72. [PMID: 33292187 PMCID: PMC7724732 DOI: 10.1186/s12711-020-00592-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 11/24/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Genetic pressure in animal breeding is sparking the interest of breeders for selecting elite boars with higher sperm quality to optimize ejaculate doses and fertility rates. However, the molecular basis of sperm quality is not yet fully understood. Our aim was to identify candidate genes, pathways and DNA variants associated to sperm quality in swine by analysing 25 sperm-related phenotypes and integrating genome-wide association studies (GWAS) and RNA-seq under a systems biology framework. RESULTS By GWAS, we identified 12 quantitative trait loci (QTL) associated to the percentage of head and neck abnormalities, abnormal acrosomes and motile spermatozoa. Candidate genes included CHD2, KATNAL2, SLC14A2 and ABCA1. By RNA-seq, we identified a wide repertoire of mRNAs (e.g. PRM1, OAZ3, DNAJB8, TPPP2 and TNP1) and miRNAs (e.g. ssc-miR-30d, ssc-miR-34c, ssc-miR-30c-5p, ssc-miR-191, members of the let-7 family and ssc-miR-425-5p) with functions related to sperm biology. We detected 6128 significant correlations (P-value ≤ 0.05) between sperm traits and mRNA abundances. By expression (e)GWAS, we identified three trans-expression QTL involving the genes IQCJ, ACTR2 and HARS. Using the GWAS and RNA-seq data, we built a gene interaction network. We considered that the genes and interactions that were present in both the GWAS and RNA-seq networks had a higher probability of being actually involved in sperm quality and used them to build a robust gene interaction network. In addition, in the final network we included genes with RNA abundances correlated with more than four semen traits and miRNAs interacting with the genes on the network. The final network was enriched for genes involved in gamete generation and development, meiotic cell cycle, DNA repair or embryo implantation. Finally, we designed a panel of 73 SNPs based on the GWAS, eGWAS and final network data, that explains between 5% (for sperm cell concentration) and 36% (for percentage of neck abnormalities) of the phenotypic variance of the sperm traits. CONCLUSIONS By applying a systems biology approach, we identified genes that potentially affect sperm quality and constructed a SNP panel that explains a substantial part of the phenotypic variance for semen quality in our study and that should be tested in other swine populations to evaluate its relevance for the pig breeding sector.
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Affiliation(s)
- Marta Gòdia
- Animal Genomics Group, Centre for Research in Agricultural Genomics (CRAG) CSIC-IRTA-UAB-UB, Campus UAB, Cerdanyola del Vallès, 08193, Barcelona, Catalonia, Spain
| | - Antonio Reverter
- CSIRO Agriculture and Food, Queensland Bioscience Precinct, 306 Carmody Rd., St. Lucia, Brisbane, QLD, 4067, Australia
| | - Rayner González-Prendes
- Animal Breeding and Genomics, Wageningen University & Research, 6708PB, Wageningen, The Netherlands
| | - Yuliaxis Ramayo-Caldas
- Animal Breeding and Genetics Program, Institute for Research and Technology in Food and Agriculture (IRTA), Torre Marimon, 08140, Caldes de Montbui, Catalonia, Spain
| | - Anna Castelló
- Animal Genomics Group, Centre for Research in Agricultural Genomics (CRAG) CSIC-IRTA-UAB-UB, Campus UAB, Cerdanyola del Vallès, 08193, Barcelona, Catalonia, Spain.,Unit of Animal Science, Department of Animal and Food Science, Autonomous University of Barcelona, Cerdanyola del Vallès, 08193, Barcelona, Catalonia, Spain
| | - Joan-Enric Rodríguez-Gil
- Unit of Animal Reproduction, Department of Animal Medicine and Surgery, Autonomous University of Barcelona, Cerdanyola del Vallès, 08193, Barcelona, Catalonia, Spain
| | - Armand Sánchez
- Unit of Animal Science, Department of Animal and Food Science, Autonomous University of Barcelona, Cerdanyola del Vallès, 08193, Barcelona, Catalonia, Spain
| | - Alex Clop
- Animal Genomics Group, Centre for Research in Agricultural Genomics (CRAG) CSIC-IRTA-UAB-UB, Campus UAB, Cerdanyola del Vallès, 08193, Barcelona, Catalonia, Spain. .,Consejo Superior de Investigaciones Científicas (CSIC), 08003, Barcelona, Catalonia, Spain.
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Qin T, Yuan Z, Yu J, Fu X, Deng X, Fu Q, Ma Z, Ma S. Saikosaponin-d impedes hippocampal neurogenesis and causes cognitive deficits by inhibiting the survival of neural stem/progenitor cells via neurotrophin receptor signaling in mice. Clin Transl Med 2020; 10:e243. [PMID: 33377633 PMCID: PMC7752162 DOI: 10.1002/ctm2.243] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 11/21/2020] [Accepted: 11/26/2020] [Indexed: 12/18/2022] Open
Abstract
Neural stem/progenitor cells (NPCs) are multipotent stem cells in the central nervous system. Damage to NPCs has been demonstrated to cause adverse effects on neurogenesis and to contribute to neurological diseases. Our previous research suggested that saikosaponin-d (SSd), a cytostatic drug belonging to the bioactive triterpenoid saponins, exhibited neurotoxicity by inhibiting hippocampal neurogenesis, but the underlying mechanism remained elusive. This study was performed to clarify the role of SSd in cognitive function and the mechanism by which SSd induced damage to hippocampal neurogenesis and NPCs. Our results indicated that SSd caused hippocampus-dependent cognitive deficits and inhibited hippocampal neurogenesis by reducing the numbers of newborn neurons in mice. RNA sequencing analysis revealed that SSd-induced neurotoxicity in the hippocampus involved neurotrophin receptor-interacting MAGE (NRAGE)/neurotrophin receptor interacting factor (NRIF)/p75NTR -associated cell death executor (NADE) cell signaling activated by the p75 neurotrophin receptor (p75NTR ). Mechanistic studies showed that a short hairpin RNA targeting p75NTR intracellular domain reversed SSd-increased NRAGE/NRIF/NADE signaling and the c-Jun N-terminal kinase/caspase apoptotic pathway, subsequently contributing to the survival of NPCs, as well as cell proliferation and differentiation. The addition of recombinant brain-derived neurotrophic factor (BDNF) ameliorated the SSd-induced inhibition of BDNF/Tyrosine kinase receptor B (TrkB) neurotrophic signaling, but did not affect SSd-activated pro-BDNF/p75NTR signaling. Moreover, the SSd-induced elevation of cytosolic Ca2+ concentration was responsible for damage to NPCs. The extracellular Ca2+ chelator ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA), rather than the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA/AM), attenuated SSd-induced cytosolic Ca2+ dysfunction and SSd-disordered TrkB/p75NTR signaling. Overall, this study demonstrated a new mechanism for the neurotoxic effect of SSd, which has emerging implications for pharmacological research of SSd and provides a better understanding of neurotoxicity induced by cytostatic drugs.
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Affiliation(s)
- Tingting Qin
- Department of Pharmacology of Chinese Materia MedicaChina Pharmaceutical UniversityNanjingChina
| | - Ziqiao Yuan
- Jiangsu Key Laboratory of Drug ScreeningChina Pharmaceutical UniversityNanjingChina
| | - Jiayu Yu
- Department of Pharmacology of Chinese Materia MedicaChina Pharmaceutical UniversityNanjingChina
| | - Xinxin Fu
- Department of Pharmacology of Chinese Materia MedicaChina Pharmaceutical UniversityNanjingChina
| | - Xueyang Deng
- Department of Pharmacology of Chinese Materia MedicaChina Pharmaceutical UniversityNanjingChina
| | - Qiang Fu
- Department of Pharmacology of Chinese Materia MedicaChina Pharmaceutical UniversityNanjingChina
| | - Zhanqiang Ma
- Department of Pharmacology of Chinese Materia MedicaChina Pharmaceutical UniversityNanjingChina
| | - Shiping Ma
- Department of Pharmacology of Chinese Materia MedicaChina Pharmaceutical UniversityNanjingChina
- Qinba Traditional Chinese Medicine Resources Research and Development CenterAnKang UniversityAnkangChina
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Gardner JC, Dvoretskiy SV, Yang Y, Venkataraman S, Lange DA, Li S, Boppart AL, Kim N, Rendeiro C, Boppart MD, Rhodes JS. Electrically stimulated hind limb muscle contractions increase adult hippocampal astrogliogenesis but not neurogenesis or behavioral performance in male C57BL/6J mice. Sci Rep 2020; 10:19319. [PMID: 33168868 PMCID: PMC7652861 DOI: 10.1038/s41598-020-76356-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 10/19/2020] [Indexed: 12/11/2022] Open
Abstract
Regular exercise is crucial for maintaining cognitive health throughout life. Recent evidence suggests muscle contractions during exercise release factors into the blood which cross into the brain and stimulate adult hippocampal neurogenesis. However, no study has tested whether muscle contractions alone are sufficient to increase adult hippocampal neurogenesis and improve behavioral performance. Adult male, C57BL/6J mice were anesthetized and exposed to bilateral hind limb muscle contractions (both concentric and eccentric) via electrical stimulation (e-stim) of the sciatic nerve twice a week for 8 weeks. Each session lasted approximately 20 min and consisted of a total of 40 muscle contractions. The control group was treated similarly except without e-stim (sham). Acute neuronal activation of the dentate gyrus (DG) using cFos immunohistochemistry was measured as a negative control to confirm that the muscle contractions did not activate the hippocampus, and in agreement, no DG activation was observed. Relative to sham, e-stim training increased DG volume by approximately 10% and astrogliogenesis by 75%, but no difference in neurogenesis was detected and no improvement in behavioral performance was observed. E-stim also increased astrogliogenesis in CA1/CA2 hippocampal subfields but not in the cortex. Results demonstrate that muscle contractions alone, in absence of DG activation, are sufficient to increase adult hippocampal astrogliogenesis, but not neurogenesis or behavioral performance in mice.
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Affiliation(s)
- Jennie C Gardner
- Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, USA.,Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, 405 N. Mathews Ave., Urbana, IL, 61801, USA
| | - Svyatoslav V Dvoretskiy
- Department of Kinesiology and Community Health, University of Illinois at Urbana Champaign, Champaign, USA.,Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, 405 N. Mathews Ave., Urbana, IL, 61801, USA
| | - Yanyu Yang
- Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, USA.,Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, 405 N. Mathews Ave., Urbana, IL, 61801, USA
| | - Sanjana Venkataraman
- Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, USA.,Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, 405 N. Mathews Ave., Urbana, IL, 61801, USA
| | - Dominica A Lange
- Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, USA.,Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, 405 N. Mathews Ave., Urbana, IL, 61801, USA
| | - Shiping Li
- Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, USA.,Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, 405 N. Mathews Ave., Urbana, IL, 61801, USA
| | - Alexandria L Boppart
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, 405 N. Mathews Ave., Urbana, IL, 61801, USA
| | - Noah Kim
- Department of Kinesiology and Community Health, University of Illinois at Urbana Champaign, Champaign, USA.,Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, 405 N. Mathews Ave., Urbana, IL, 61801, USA
| | - Catarina Rendeiro
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, 405 N. Mathews Ave., Urbana, IL, 61801, USA.,School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK
| | - Marni D Boppart
- Department of Kinesiology and Community Health, University of Illinois at Urbana Champaign, Champaign, USA.,Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, 405 N. Mathews Ave., Urbana, IL, 61801, USA
| | - Justin S Rhodes
- Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, USA. .,Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, 405 N. Mathews Ave., Urbana, IL, 61801, USA.
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Colucci-D’Amato L, Speranza L, Volpicelli F. Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer. Int J Mol Sci 2020; 21:E7777. [PMID: 33096634 PMCID: PMC7589016 DOI: 10.3390/ijms21207777] [Citation(s) in RCA: 506] [Impact Index Per Article: 101.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/16/2020] [Accepted: 10/19/2020] [Indexed: 01/10/2023] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is one of the most distributed and extensively studied neurotrophins in the mammalian brain. BDNF signals through the tropomycin receptor kinase B (TrkB) and the low affinity p75 neurotrophin receptor (p75NTR). BDNF plays an important role in proper growth, development, and plasticity of glutamatergic and GABAergic synapses and through modulation of neuronal differentiation, it influences serotonergic and dopaminergic neurotransmission. BDNF acts as paracrine and autocrine factor, on both pre-synaptic and post-synaptic target sites. It is crucial in the transformation of synaptic activity into long-term synaptic memories. BDNF is considered an instructive mediator of functional and structural plasticity in the central nervous system (CNS), influencing dendritic spines and, at least in the hippocampus, the adult neurogenesis. Changes in the rate of adult neurogenesis and in spine density can influence several forms of learning and memory and can contribute to depression-like behaviors. The possible roles of BDNF in neuronal plasticity highlighted in this review focus on the effect of antidepressant therapies on BDNF-mediated plasticity. Moreover, we will review data that illustrate the role of BDNF as a potent protective factor that is able to confer protection against neurodegeneration, in particular in Alzheimer's disease. Finally, we will give evidence of how the involvement of BDNF in the pathogenesis of brain glioblastoma has emerged, thus opening new avenues for the treatment of this deadly cancer.
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Affiliation(s)
- Luca Colucci-D’Amato
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
- InterUniversity Center for Research in Neurosciences (CIRN), University of Campania "Luigi Vanvitelli", 80131 Naples, Italy
| | - Luisa Speranza
- Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461, USA;
| | - Floriana Volpicelli
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy;
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Armstrong NJ, Mather KA, Sargurupremraj M, Knol MJ, Malik R, Satizabal CL, Yanek LR, Wen W, Gudnason VG, Dueker ND, Elliott LT, Hofer E, Bis J, Jahanshad N, Li S, Logue MA, Luciano M, Scholz M, Smith AV, Trompet S, Vojinovic D, Xia R, Alfaro-Almagro F, Ames D, Amin N, Amouyel P, Beiser AS, Brodaty H, Deary IJ, Fennema-Notestine C, Gampawar PG, Gottesman R, Griffanti L, Jack CR, Jenkinson M, Jiang J, Kral BG, Kwok JB, Lampe L, C M Liewald D, Maillard P, Marchini J, Bastin ME, Mazoyer B, Pirpamer L, Rafael Romero J, Roshchupkin GV, Schofield PR, Schroeter ML, Stott DJ, Thalamuthu A, Trollor J, Tzourio C, van der Grond J, Vernooij MW, Witte VA, Wright MJ, Yang Q, Morris Z, Siggurdsson S, Psaty B, Villringer A, Schmidt H, Haberg AK, van Duijn CM, Jukema JW, Dichgans M, Sacco RL, Wright CB, Kremen WS, Becker LC, Thompson PM, Mosley TH, Wardlaw JM, Ikram MA, Adams HHH, Seshadri S, Sachdev PS, Smith SM, Launer L, Longstreth W, DeCarli C, Schmidt R, Fornage M, Debette S, Nyquist PA. Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities. Stroke 2020; 51:2111-2121. [PMID: 32517579 DOI: 10.1161/strokeaha.119.027544] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND PURPOSE Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. METHODS Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. RESULTS In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. CONCLUSIONS Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.
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Affiliation(s)
- Nicola J Armstrong
- Mathematics and Statistics, Murdoch University, Perth, Australia (N.J.A.)
| | - Karen A Mather
- Centre for Healthy Brain Ageing, School of Psychiatry (K.A.M., W.W., H.B., J.J., A.T., J.T., P.S.S.), University of New South Wales, Sydney, Australia.,Neuroscience Research Australia, Sydney, Australia (K.A.M., P.R.S., A.T.)
| | | | - Maria J Knol
- Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands (M.J.K., D.V., N.A., G.V.R., M.W.V., C.M.v.D., M.A.I., H.H.H.A.)
| | - Rainer Malik
- Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-Universität LMU Munich, Germany (R.M., M.D.)
| | - Claudia L Satizabal
- Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX (C.L.S., S.S.).,The Framingham Heart Study, MA (C.L.S., A.S.B., J.R.R., S.S.).,Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA
| | - Lisa R Yanek
- GeneSTAR Research Program (L.R.Y., B.G.K., L.C.B., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD
| | - Wei Wen
- Centre for Healthy Brain Ageing, School of Psychiatry (K.A.M., W.W., H.B., J.J., A.T., J.T., P.S.S.), University of New South Wales, Sydney, Australia
| | - Vilmundur G Gudnason
- Icelandic Heart Association, Kopavogur (V.G.G., S.S.).,University of Iceland, Reykjavik, Iceland (V.G.G., A.V.S.)
| | - Nicole D Dueker
- Dr. John T. Macdonald Foundation Department of Human Genetics (R.L.S.), University of Miami, FL
| | - Lloyd T Elliott
- Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, BC, Canada (L.T.E.).,Wellcome Centre for Integrative Neuroimaging (WIN FMRIB) (L.T.E., F.A.-A., L.G., M.J., S.M.S.), University of Oxford, United Kingdom
| | - Edith Hofer
- Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (E.H., R.S.).,Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria (E.H.)
| | - Joshua Bis
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA (J.B., B.P., W.L.)
| | - Neda Jahanshad
- Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Marina del Rey (N.J., P.M.T.)
| | - Shuo Li
- Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.)
| | - Mark A Logue
- Department of Psychiatry and Biomedical Genetics Section (M.A.L.), Boston University School of Medicine, MA.,Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.).,National Center for PTSD: Behavioral Science Division, VA Boston Healthcare System, Boston, MA (M.A.L.)
| | - Michelle Luciano
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, United Kingdom (M.L., I.J.D., D.C.M.L., M.E.B., J.M.W.)
| | - Markus Scholz
- Institute for Medical Informatics, Statistics and Epidemiology (M.S.)
| | - Albert V Smith
- University of Iceland, Reykjavik, Iceland (V.G.G., A.V.S.)
| | - Stella Trompet
- Department of Internal Medicine, Section of Gerontology and Geriatrics (S.T.), Leiden University Medical Center, the Netherlands.,Department of Cardiology (S.T.), Leiden University Medical Center, the Netherlands
| | - Dina Vojinovic
- Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands (M.J.K., D.V., N.A., G.V.R., M.W.V., C.M.v.D., M.A.I., H.H.H.A.)
| | - Rui Xia
- Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, TX (R.X., M.F.)
| | - Fidel Alfaro-Almagro
- Wellcome Centre for Integrative Neuroimaging (WIN FMRIB) (L.T.E., F.A.-A., L.G., M.J., S.M.S.), University of Oxford, United Kingdom
| | - David Ames
- National Ageing Research Institute, Parkville, Victoria, Australia (D.A.).,Academic Unit for Psychiatry of Old Age, University of Melbourne, St George's Hospital, Kew, Australia (D.A.)
| | - Najaf Amin
- Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands (M.J.K., D.V., N.A., G.V.R., M.W.V., C.M.v.D., M.A.I., H.H.H.A.)
| | - Philippe Amouyel
- Lille University, Inserm, Institut Pasteur de Lille, RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases and Labex Distalz, France (P.A.).,Lille University, Inserm, CHU Lille, Institut Pasteur de Lille, RID-AGE (P.A.)
| | - Alexa S Beiser
- The Framingham Heart Study, MA (C.L.S., A.S.B., J.R.R., S.S.).,Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA.,Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.)
| | - Henry Brodaty
- Centre for Healthy Brain Ageing, School of Psychiatry (K.A.M., W.W., H.B., J.J., A.T., J.T., P.S.S.), University of New South Wales, Sydney, Australia.,Dementia Centre for Research Collaboration (H.B.), University of New South Wales, Sydney, Australia
| | - Ian J Deary
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, United Kingdom (M.L., I.J.D., D.C.M.L., M.E.B., J.M.W.)
| | - Christine Fennema-Notestine
- Department of Psychiatry (C.F.-N.), University of California, San Diego, La Jolla, CA.,Center for Behavior Genetics of Aging (C.F.-N.), University of California, San Diego, La Jolla, CA
| | - Piyush G Gampawar
- Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Medical University of Graz, Austria (P.G.G., H.S.)
| | - Rebecca Gottesman
- Department of Neurology, Cerebrovascular and stroke Division (R.G.), Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ludovica Griffanti
- Wellcome Centre for Integrative Neuroimaging (WIN FMRIB) (L.T.E., F.A.-A., L.G., M.J., S.M.S.), University of Oxford, United Kingdom
| | - Clifford R Jack
- Department of Radiology, Mayo Clinic, Rochester, MN (C.R.J.J.)
| | - Mark Jenkinson
- Wellcome Centre for Integrative Neuroimaging (WIN FMRIB) (L.T.E., F.A.-A., L.G., M.J., S.M.S.), University of Oxford, United Kingdom
| | - Jiyang Jiang
- Centre for Healthy Brain Ageing, School of Psychiatry (K.A.M., W.W., H.B., J.J., A.T., J.T., P.S.S.), University of New South Wales, Sydney, Australia
| | - Brian G Kral
- GeneSTAR Research Program (L.R.Y., B.G.K., L.C.B., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD
| | - John B Kwok
- School of Medical Sciences (J.B.K., P.R.S.), University of New South Wales, Sydney, Australia.,Brain and Mind Centre - The University of Sydney, Camperdown, NSW, Australia (J.B.K.)
| | - Leonie Lampe
- Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (L.L., V.A.W.)
| | - David C M Liewald
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, United Kingdom (M.L., I.J.D., D.C.M.L., M.E.B., J.M.W.)
| | - Pauline Maillard
- Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology, University of California-Davis, Davis, CA (P.M.)
| | - Jonathan Marchini
- Statistical Genetics and Methods at Regeneron Pharmaceuticals, Inc, New York, NY (J.M.)
| | - Mark E Bastin
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, United Kingdom (M.L., I.J.D., D.C.M.L., M.E.B., J.M.W.).,Centre for Clinical Brain Sciences, Edinburgh Imaging, Centre for Cognitive Ageing, University of Edinburgh, United Kingdom (M.E.B., J.M.W.)
| | - Bernard Mazoyer
- Institut des Maladies Neurodégénératives, University of Bordeaux, France (B.M.)
| | - Lukas Pirpamer
- Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (L.P.)
| | - José Rafael Romero
- The Framingham Heart Study, MA (C.L.S., A.S.B., J.R.R., S.S.).,Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA
| | - Gennady V Roshchupkin
- Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands (M.J.K., D.V., N.A., G.V.R., M.W.V., C.M.v.D., M.A.I., H.H.H.A.).,Department of Radiology and Nuclear Medicine (G.V.R., M.W.V., H.H.H.A.)
| | - Peter R Schofield
- School of Medical Sciences (J.B.K., P.R.S.), University of New South Wales, Sydney, Australia.,Neuroscience Research Australia, Sydney, Australia (K.A.M., P.R.S., A.T.)
| | - Matthias L Schroeter
- LIFE Research Center for Civilization Disease, Leipzig, Germany (M.S.).,Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (M.L.S., A.V.).,Day Clinic for Cognitive Neurology, University Hospital Leipzig, Germany (M.L.S., A.V.)
| | - David J Stott
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom (D.J.S.)
| | - Anbupalam Thalamuthu
- Centre for Healthy Brain Ageing, School of Psychiatry (K.A.M., W.W., H.B., J.J., A.T., J.T., P.S.S.), University of New South Wales, Sydney, Australia.,Neuroscience Research Australia, Sydney, Australia (K.A.M., P.R.S., A.T.)
| | - Julian Trollor
- Centre for Healthy Brain Ageing, School of Psychiatry (K.A.M., W.W., H.B., J.J., A.T., J.T., P.S.S.), University of New South Wales, Sydney, Australia.,Department of Developmental Disability Neuropsychiatry, School of Psychiatry (J.T.), University of New South Wales, Sydney, Australia
| | - Christophe Tzourio
- University Bordeaux, Inserm, Bordeaux Population Health Research Center, France (M.S., C.T., S.D.).,CHU de Bordeaux, Public Health Department, Medical information Department, Bordeaux, France (C.T.)
| | - Jeroen van der Grond
- Department of Radiology (J.v.d.G.), Leiden University Medical Center, the Netherlands
| | - Meike W Vernooij
- Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands (M.J.K., D.V., N.A., G.V.R., M.W.V., C.M.v.D., M.A.I., H.H.H.A.).,Department of Radiology and Nuclear Medicine (G.V.R., M.W.V., H.H.H.A.)
| | - Veronica A Witte
- Collaborative Research Center 1052 Obesity Mechanisms, Faculty of Medicine, University of Leipzig, Germany (V.A.W).,Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (L.L., V.A.W.)
| | - Margaret J Wright
- Queensland Brain Institute (M.J.W.), The University of Queensland, St Lucia, QLD, Australia.,Centre for Advanced Imaging (M.J.W.), The University of Queensland, St Lucia, QLD, Australia
| | - Qiong Yang
- Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.)
| | - Zoe Morris
- Neuroradiology Department, Department of Clinical Neurosciences, Western General Hospital, Edinburgh, United Kingdom (Z.M.)
| | - Siggi Siggurdsson
- Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX (C.L.S., S.S.).,The Framingham Heart Study, MA (C.L.S., A.S.B., J.R.R., S.S.).,Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA
| | - Bruce Psaty
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA (J.B., B.P., W.L.)
| | - Arno Villringer
- Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (M.L.S., A.V.).,Day Clinic for Cognitive Neurology, University Hospital Leipzig, Germany (M.L.S., A.V.)
| | - Helena Schmidt
- Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Medical University of Graz, Austria (P.G.G., H.S.)
| | - Asta K Haberg
- Department of Neuromedicine and Movement Science (A.K.H.), Norwegian University of Science and Technology, Trondheim, Norway.,Department of Radiology and Nuclear Medicine (A.K.H.), Norwegian University of Science and Technology, Trondheim, Norway
| | - Cornelia M van Duijn
- Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands (M.J.K., D.V., N.A., G.V.R., M.W.V., C.M.v.D., M.A.I., H.H.H.A.).,Nuffield Department of Population Health (C.M.v.D.), University of Oxford, United Kingdom
| | - J Wouter Jukema
- Department of Cardiology (J.W.J.), Leiden University Medical Center, the Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, the Netherlands (J.W.J.)
| | - Martin Dichgans
- Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-Universität LMU Munich, Germany (R.M., M.D.).,German Center for Neurodegenerative Diseases, Munich, Germany (M.D.).,Munich Cluster for Systems Neurology (SyNergy), Germany (M.D.)
| | - Ralph L Sacco
- Department of Public Health Sciences, Miller School of Medicine (R.L.S.), University of Miami, FL.,Department of Neurology, Miller School of Medicine (R.L.S.), University of Miami, FL.,Evelyn F. McKnight Brain Institute, Department of Neurology (R.L.S.), University of Miami, FL
| | - Clinton B Wright
- National Institute of Neurological Disorders and Stroke (C.B.W.), National Institutes of Health, Bethesda, MD
| | - William S Kremen
- Center for Behavior Genetics of Aging (W.S.K.), University of California, San Diego, La Jolla, CA.,Department of Psychiatry (W.S.K.), University of California, San Diego, La Jolla, CA
| | - Lewis C Becker
- GeneSTAR Research Program (L.R.Y., B.G.K., L.C.B., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD
| | - Paul M Thompson
- Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Marina del Rey (N.J., P.M.T.)
| | - Thomas H Mosley
- Department of Geriatric Medicine, Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center, Jackson (T.H.M.)
| | - Joanna M Wardlaw
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, United Kingdom (M.L., I.J.D., D.C.M.L., M.E.B., J.M.W.).,Centre for Clinical Brain Sciences, Edinburgh Imaging, Centre for Cognitive Ageing, University of Edinburgh, United Kingdom (M.E.B., J.M.W.)
| | - M Arfan Ikram
- Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands (M.J.K., D.V., N.A., G.V.R., M.W.V., C.M.v.D., M.A.I., H.H.H.A.)
| | - Hieab H H Adams
- Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands (M.J.K., D.V., N.A., G.V.R., M.W.V., C.M.v.D., M.A.I., H.H.H.A.).,Department of Radiology and Nuclear Medicine (G.V.R., M.W.V., H.H.H.A.).,Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands (H.H.H.A.)
| | | | - Perminder S Sachdev
- Centre for Healthy Brain Ageing, School of Psychiatry (K.A.M., W.W., H.B., J.J., A.T., J.T., P.S.S.), University of New South Wales, Sydney, Australia.,Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia (P.S.S.)
| | - Stephen M Smith
- Wellcome Centre for Integrative Neuroimaging (WIN FMRIB) (L.T.E., F.A.-A., L.G., M.J., S.M.S.), University of Oxford, United Kingdom
| | - Lenore Launer
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program (L.L.), National Institutes of Health, Bethesda, MD
| | - William Longstreth
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA (J.B., B.P., W.L.)
| | - Charles DeCarli
- Alzheimer's Disease Center and Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology and Center for Neuroscience University of California at Davis (C.D.)
| | - Reinhold Schmidt
- Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (E.H., R.S.)
| | - Myriam Fornage
- Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, TX (R.X., M.F.).,Human Genetics Center, School of Public Health UT, Houston, TX (M.F.)
| | - Stephanie Debette
- University Bordeaux, Inserm, Bordeaux Population Health Research Center, France (M.S., C.T., S.D.).,Department of Neurology, CHU de Bordeaux (University Hospital), Bordeaux, France (S.D.)
| | - Paul A Nyquist
- GeneSTAR Research Program (L.R.Y., B.G.K., L.C.B., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD.,Departments of Neurology, Critical Care Medicine, Neurosurgery (P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD.,Critical Care Medicine Department (P.A.N.), National Institutes of Health, Bethesda, MD
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39
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Chen LF, Lyons MR, Liu F, Green MV, Hedrick NG, Williams AB, Narayanan A, Yasuda R, West AE. The NMDA receptor subunit GluN3A regulates synaptic activity-induced and myocyte enhancer factor 2C (MEF2C)-dependent transcription. J Biol Chem 2020; 295:8613-8627. [PMID: 32393578 DOI: 10.1074/jbc.ra119.010266] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 05/01/2020] [Indexed: 11/06/2022] Open
Abstract
N-Methyl-d-aspartate type glutamate receptors (NMDARs) are key mediators of synaptic activity-regulated gene transcription in neurons, both during development and in the adult brain. Developmental differences in the glutamate receptor ionotropic NMDA 2 (GluN2) subunit composition of NMDARs determines whether they activate the transcription factor cAMP-responsive element-binding protein 1 (CREB). However, whether the developmentally regulated GluN3A subunit also modulates NMDAR-induced transcription is unknown. Here, using an array of techniques, including quantitative real-time PCR, immunostaining, reporter gene assays, RNA-Seq, and two-photon glutamate uncaging with calcium imaging, we show that knocking down GluN3A in rat hippocampal neurons promotes the inducible transcription of a subset of NMDAR-sensitive genes. We found that this enhancement is mediated by the accumulation of phosphorylated p38 mitogen-activated protein kinase in the nucleus, which drives the activation of the transcription factor myocyte enhancer factor 2C (MEF2C) and promotes the transcription of a subset of synaptic activity-induced genes, including brain-derived neurotrophic factor (Bdnf) and activity-regulated cytoskeleton-associated protein (Arc). Our evidence that GluN3A regulates MEF2C-dependent transcription reveals a novel mechanism by which NMDAR subunit composition confers specificity to the program of synaptic activity-regulated gene transcription in developing neurons.
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Affiliation(s)
- Liang-Fu Chen
- Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA
| | - Michelle R Lyons
- Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA
| | - Fang Liu
- Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA
| | - Matthew V Green
- Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA
| | - Nathan G Hedrick
- Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA
| | - Ashley B Williams
- Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA
| | - Arthy Narayanan
- Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA
| | - Ryohei Yasuda
- Max Planck Florida Institute for Neuroscience, Jupiter, Florida, USA
| | - Anne E West
- Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA
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40
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Park J, Cheon W, Kim K. Effects of Long-Term Endurance Exercise and Lithium Treatment on Neuroprotective Factors in Hippocampus of Obese Rats. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17093317. [PMID: 32397675 PMCID: PMC7246857 DOI: 10.3390/ijerph17093317] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/06/2020] [Accepted: 05/07/2020] [Indexed: 01/03/2023]
Abstract
To investigate the effects of long-term lithium treatment and low intensity endurance exercise on brain-derived neurotrophic factor (BDNF) expression and glycogen synthase kinase 3 beta (GSK3β) activity in the hippocampus of obese rats. Fifty 10-week-old male Sprague-Dawley rats were selected. There was a control group of 10 rats (chow control group) while the other forty rats were fed on a high-fat diet for eight weeks to induce obesity. Rats were then assigned into four random groups. The rats were given 10 mg/kg lithium chloride (LiCl) dissolved in 1 mL sterile distilled water once a day, 5 times a week. The rats did 20 min of treadmill walking with an exercise intensity of 40% maximal oxygen uptake (VO2 max) (12 m/min, slope 0%). This was performed for 20 min a day, 3 days a week. Twelve weeks of lithium treatment or endurance exercise significantly reduced body weight and body fat mass in obese rats, without showing additive effects when the treatments were given in parallel or significant toxic responses in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in blood and kidney and liver tissues. BDNF expression in the hippocampus was significantly increased both in exercise and lithium groups with synergistic effects found in the group where both exercise and lithium treatments were given in parallel. On the other hand, the decrease in GSK3β activity was shown only in the lithium treatment group, without showing additive effects when the treatments were given in parallel. Lithium and low-intensity endurance exercise for 12 weeks increased the expression of BDNF, a neuroprotective factor in the hippocampus of obese mice. Lithium treatment alone inhibited the activity of GSK3β. This can be interpreted as a positive indication of applicability of the two factors in the prevention of neurodegenerative diseases.
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Affiliation(s)
- Jusik Park
- Department of Taekwondo, College of Physical Education, Keimyung University, Daegu 42601, Korea;
| | - Wookwang Cheon
- Department of Physical Education, College of Physical Education, Keimyung University, Daegu 42601, Korea;
| | - Kijin Kim
- Department of Physical Education, College of Physical Education, Keimyung University, Daegu 42601, Korea;
- Correspondence: ; Tel.: +82-53-580-5256
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41
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Wu Z, Bai L, Tu R, Zhang L, Ba Y, Zhang H, Li X, Cheng X, Li W, Huang H. Disruption of synaptic expression pattern and age-related DNA oxidation in a neuronal model of lead-induced toxicity. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2020; 76:103350. [PMID: 32058320 DOI: 10.1016/j.etap.2020.103350] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 01/18/2020] [Accepted: 02/03/2020] [Indexed: 06/10/2023]
Abstract
Lead (Pb) is recognized as a potent inducer of synaptic toxicity generally associated with reduced synaptic transmission and increased neuronal fiber excitability, becoming an environmental risk for neurodegenerative processes. Despite numerous toxicological studies on Pb have been directed to the developing brain, attention concerning long-term consequences of pubertal chronic Pb exposure on neuronal activity is still lacking. Thus, we exposed 4-week-old male mice to 0.2 % lead acetate solution for one month, then, conducted behavioral tests or extracted brain homogenate from mice prefrontal cortex (PFC) and hippocampus at the age of 4, 13 and 16-month-old respectively. Our results showed that treated mice exhibited an evident increase in latency to reach platform following pubertal Pb exposure and aging. The increase of 8-OHdG revealed evident neural DNA oxidative damage across time upon pubertal Pb exposure. In the hippocampus of lead exposed mice at three age nodes, the expression of brain-derived neurotrophic factor precursor (proBDNF) increased, while that of mature BDNF (mBDNF), cAMP-response element binding protein (CREB) and phosphorylated CREB (pCREB) decreased compared with the control group. Furthermore, the expression of BACE1 protein and tau phosphorylation level in PFC and hippocampus increased, APP mRNAs in PFC and prolonged induction of BACE1 in hippocampus. Our results show that chronic Pb exposure from pubertal stage onward can either initiate divergent synaptic-related gene expression patterns in adulthood or trigger time-course of neurodegenerative profile within the PFC or hippocampus, which can contribute consistent deficits of cognition across subsequent age-nodes.
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Affiliation(s)
- Zuntao Wu
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Lin Bai
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Runqi Tu
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Lijie Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Yue Ba
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Huizhen Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Xing Li
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Xuemin Cheng
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Wenjie Li
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Hui Huang
- College of Public Health, Zhengzhou University, Zhengzhou, PR China.
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42
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Fukuchi M. Identifying inducers of BDNF gene expression from pharmacologically validated compounds; antipyretic drug dipyrone increases BDNF mRNA in neurons. Biochem Biophys Res Commun 2020; 524:957-962. [PMID: 32059848 DOI: 10.1016/j.bbrc.2020.02.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 02/05/2020] [Indexed: 12/11/2022]
Abstract
Low levels of brain-derived neurotrophic factor (BDNF), a key regulator of synaptic plasticity, are associated with neurological diseases, including depression and Alzheimer's disease. Therefore, BDNF is a drug target for these diseases. Here we screened for inducers of neuronal Bdnf expression from a pharmacologically validated compound library using our recently developed screening assay based on luciferase activity in cultured cortical neurons. We identified 18 pharmacologically validated compounds, most of which were inferred to induce Bdnf expression by their validated pharmacological actions, such as Gs-coupled receptor activation or neuronal excitation. Unexpectedly, the screening assay identified the antipyretic drug, dipyrone, to increase Bdnf expression. Dipyrone induced endogenous Bdnf expression by Ca2+ influx evoked via L-type voltage-dependent Ca2+ channels and the N-methyl-d-aspartate receptor, indicating that dipyrone induced activity-regulated Bdnf expression in neurons. However, dipyrone-induced Bdnf expression is independent of validated pharmacological effects. Although our screening assay is difficult to reveal how active compounds induce Bdnf expression, this method is convenient to identify inducers of Bdnf expression in primary neurons. Our screening assay evaluated neuronal BDNF induction and can be used to screen for drug re-positioning, as well as novel candidate drugs, for neurological diseases that have low levels of BDNF in the brain.
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Affiliation(s)
- Mamoru Fukuchi
- Laboratory of Molecular Neuroscience, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki-shi, Gunma, 370-0033, Japan.
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43
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Atone J, Wagner K, Hashimoto K, Hammock BD. Cytochrome P450 derived epoxidized fatty acids as a therapeutic tool against neuroinflammatory diseases. Prostaglandins Other Lipid Mediat 2020; 147:106385. [PMID: 31698143 PMCID: PMC7067627 DOI: 10.1016/j.prostaglandins.2019.106385] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 07/26/2019] [Accepted: 08/08/2019] [Indexed: 12/23/2022]
Abstract
Cytochrome P450 (CYP) metabolism of arachidonic acid (ARA) produces epoxy fatty acids (EpFAs) such as epoxyeicosatrienoic acids (EETs) that are known to exert protective effects in inflammatory disorders. Endogenous EpFAs are further metabolized into corresponding diols by the soluble epoxide hydrolase (sEH). Through inhibition of sEH, many studies have demonstrated the cardioprotective and renoprotective effects of EpFAs; however, the role of sEH inhibition in modulating the pathogenesis of neuroinflammatory disorders is less well described. In this review, we discuss the current knowledge surrounding the effects of sEH inhibition and EpFA action in neuroinflammatory disorders such as Parkinson's Disease (PD), stroke, depression, epilepsy, and Alzheimer's Disease (AD), as well as the potential mechanisms that underlie the therapeutic effects of sEH inhibition.
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Affiliation(s)
- Jogen Atone
- Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, United States
| | - Karen Wagner
- Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, United States
| | - Kenji Hashimoto
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan
| | - Bruce D Hammock
- Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, United States.
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Snyder MA, Gao WJ. NMDA receptor hypofunction for schizophrenia revisited: Perspectives from epigenetic mechanisms. Schizophr Res 2020; 217:60-70. [PMID: 30979669 PMCID: PMC7258307 DOI: 10.1016/j.schres.2019.03.010] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 03/08/2019] [Accepted: 03/11/2019] [Indexed: 02/06/2023]
Abstract
Schizophrenia (SZ) is a neurodevelopmental disorder with cognitive deficits manifesting during early stages of the disease. Evidence suggests that genetic factors in combination with environmental insults lead to complex changes to glutamatergic, GABAergic, and dopaminergic systems. In particular, the N-methyl-d-aspartate receptor (NMDAR), a major glutamate receptor subtype, is implicated in both the disease progression and symptoms of SZ. NMDARs are critical for synaptic plasticity and cortical maturation, as well as learning and memory processes. In fact, any deviation from normal NMDAR expression and function can have devastating consequences. Surprisingly, there is little evidence from human patients that direct mutations of NMDAR genes contribute to SZ. One intriguing hypothesis is that epigenetic changes, which could result from early insults, alter protein expression and contribute to the NMDAR hypofunction found in SZ. Epigenetics is referred to as modifications that alter gene transcription without changing the DNA sequence itself. In this review, we first discuss how epigenetic changes to NMDAR genes could contribute to NMDAR hypofunction. We then explore how NMDAR hypofunction may contribute to epigenetic changes in other proteins or genes that lead to synaptic dysfunction and symptoms in SZ. We argue that NMDAR hypofunction occurs in early stage of the disease, and it may consequentially initiate GABA and dopamine deficits. Therefore, targeting NMDAR dysfunction during the early stages would be a promising avenue for prevention and therapeutic intervention of cognitive and social deficits that remain untreatable. Finally, we discuss potential questions regarding the epigenetic of SZ and future directions for research.
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Affiliation(s)
- Melissa A. Snyder
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, K1H 8M5,Correspondence: Wen-Jun Gao, M.D., Ph.D., Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, Phone: (215) 991-8907, Fax: (215) 843-9802, ; Melissa A. Snyder, Ph.D.,
| | - Wen-Jun Gao
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, United States of America.
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McAllister BB, Bihelek N, Mychasiuk R, Dyck RH. Brain-derived Neurotrophic Factor and TrkB Levels in Mice that Lack Vesicular Zinc: Effects of Age and Sex. Neuroscience 2020; 425:90-100. [PMID: 31785352 DOI: 10.1016/j.neuroscience.2019.11.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 11/19/2022]
Abstract
In certain neurons, zinc ions are stored in synaptic vesicles by zinc transporter 3 (ZnT3). Vesicular zinc can then be released synaptically to modulate myriad targets. In vitro evidence indicates that these targets may include brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB). But the effects of vesicular zinc on BDNF and TrkB in the intact brain are unclear. Studies of mice that lack ZnT3 - and, as a result, vesicular zinc - have shown abnormalities in BDNF and TrkB levels, but results have been mixed and are therefore difficult to interpret. This might be caused by differences in the age or sex of mice tested. In the present study, we measured BDNF and TrkB levels in the hippocampus and neocortex, comparing wild type and ZnT3 knockout mice of both sexes at two ages (5 and 12 weeks). We also examined BDNF mRNA expression and protein levels at an intermediate age (8-10 weeks). We found that, regardless of age or sex, BDNF and TrkB protein levels did not differ between wild type and ZnT3 knockout mice. There were sex-specific differences in BDNF protein and mRNA expression, however. BDNF protein levels increased with age in female mice but not in males. And in females, but not males, ZnT3 KO mice exhibited great hippocampal BDNF mRNA expression than wild type mice. We conclude that, at least in naïve mice housed under standard laboratory conditions, elimination of vesicular zinc does not affect BDNF or TrkB protein levels.
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Affiliation(s)
- Brendan B McAllister
- Department of Psychology, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada; Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada
| | - Nicoline Bihelek
- Department of Psychology, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada; Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada
| | - Richelle Mychasiuk
- Department of Psychology, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada; Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada
| | - Richard H Dyck
- Department of Psychology, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada; Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.
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Rienecker KDA, Poston RG, Saha RN. Merits and Limitations of Studying Neuronal Depolarization-Dependent Processes Using Elevated External Potassium. ASN Neuro 2020; 12:1759091420974807. [PMID: 33256465 PMCID: PMC7711227 DOI: 10.1177/1759091420974807] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/07/2020] [Accepted: 10/22/2020] [Indexed: 01/24/2023] Open
Abstract
Elevated extracellular potassium chloride is widely used to achieve membrane depolarization of cultured neurons. This technique has illuminated mechanisms of calcium influx through L-type voltage sensitive calcium channels, activity-regulated signaling, downstream transcriptional events, and many other intracellular responses to depolarization. However, there is enormous variability in these treatments, including durations from seconds to days and concentrations from 3mM to 150 mM KCl. Differential effects of these variable protocols on neuronal activity and transcriptional programs are underexplored. Furthermore, potassium chloride treatments in vitro are criticized for being poor representatives of in vivo phenomena and are questioned for their effects on cell viability. In this review, we discuss the intracellular consequences of elevated extracellular potassium chloride treatment in vitro, the variability of such treatments in the literature, the strengths and limitations of this tool, and relevance of these studies to brain functions and dysfunctions.
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Affiliation(s)
- Kira D. A. Rienecker
- Department of Molecular and Cell Biology,
School of Natural Sciences, University of California, Merced, United
States
| | - Robert G. Poston
- Department of Molecular and Cell Biology,
School of Natural Sciences, University of California, Merced, United
States
| | - Ramendra N. Saha
- Department of Molecular and Cell Biology,
School of Natural Sciences, University of California, Merced, United
States
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Louis Sam Titus ASC, Sharma D, Kim MS, D'Mello SR. The Bdnf and Npas4 genes are targets of HDAC3-mediated transcriptional repression. BMC Neurosci 2019; 20:65. [PMID: 31883511 PMCID: PMC6935488 DOI: 10.1186/s12868-019-0546-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 12/18/2019] [Indexed: 12/14/2022] Open
Abstract
Background Histone deacetylase-3 (HDAC3) promotes neurodegeneration in various cell culture and in vivo models of neurodegeneration but the mechanism by which HDAC3 exerts neurotoxicity is not known. HDAC3 is known to be a transcriptional co-repressor. The goal of this study was to identify transcriptional targets of HDAC3 in an attempt to understand how it promotes neurodegeneration. Results We used chromatin immunoprecipitation analysis coupled with deep sequencing (ChIP-Seq) to identify potential targets of HDAC3 in cerebellar granule neurons. One of the genes identified was the activity-dependent and neuroprotective transcription factor, Neuronal PAS Domain Protein 4 (Npas4). We confirmed using ChIP that in healthy neurons HDAC3 associates weakly with the Npas4 promoter, however, this association is robustly increased in neurons primed to die. We find that HDAC3 also associates differentially with the brain-derived neurotrophic factor (Bdnf) gene promoter, with higher association in dying neurons. In contrast, association of HDAC3 with the promoters of other neuroprotective genes, including those encoding c-Fos, FoxP1 and Stat3, was barely detectable in both healthy and dying neurons. Overexpression of HDAC3 leads to a suppression of Npas4 and Bdnf expression in cortical neurons and treatment with RGFP966, a chemical inhibitor of HDAC3, resulted in upregulation of their expression. Expression of HDAC3 also repressed Npas4 and Bdnf promoter activity. Conclusion Our results suggest that Bdnf and Npas4 are transcriptional targets of Hdac3-mediated repression. HDAC3 inhibitors have been shown to protect against behavioral deficits and neuronal loss in mouse models of neurodegeneration and it is possible that these inhibitors work by upregulating neuroprotective genes like Bdnf and Npas4.
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Affiliation(s)
- Anto Sam Crosslee Louis Sam Titus
- Department of Biological Sciences, Southern Methodist University, Dallas, TX, USA.,Department of Biomedical Engineering, University of Houston, Houston, TX, USA
| | - Dharmendra Sharma
- Department of Biological Sciences, Southern Methodist University, Dallas, TX, USA.,Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USA
| | - Min Soo Kim
- Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Santosh R D'Mello
- Department of Biological Sciences, Southern Methodist University, Dallas, TX, USA. .,, Dallas, TX, 75243, USA.
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Venezia AC, Hyer MM, Glasper ER, Roth SM, Quinlan EM. Acute forced exercise increases Bdnf IV mRNA and reduces exploratory behavior in C57BL/6J mice. GENES BRAIN AND BEHAVIOR 2019; 19:e12617. [PMID: 31621198 DOI: 10.1111/gbb.12617] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 10/08/2019] [Accepted: 10/10/2019] [Indexed: 12/25/2022]
Abstract
Acute exercise has been shown to improve memory in humans. Potential mechanisms include increased Bdnf expression, noradrenergic activity and modification of glutamate receptors. Because mice are commonly used to study exercise and brain plasticity, it is important to explore how acute exercise impacts behavior in this model. C57BL/6J mice were assigned to three groups: control, moderate-intensity running, and high-intensity running. Control mice were placed on a stationary treadmill for 30 minutes and moderate- and high-intensity mice ran for 30 minutes at 12 and 15-17 m/min, respectively. Mice were sacrificed immediately after running and the hippocampus removed. Total Bdnf, Bdnf exon IV, and glutamate receptor subunits were quantified with quantitative polymerase chain reaction. Total and phosphorylated GluR1 (Ser845 and Ser831) protein was quantified following immunoblotting. Utilizing the same protocol for control and high-intensity running, object location memory was examined in a separate cohort of mice. Anxiety-like behavior was assessed in the open field task (OFT) in a third cohort of mice that were separated into four groups: control-saline, control-DSP-4, acute exercise-saline, and acute exercise-DSP-4. DSP-4 was used to lesion the central noradrenergic system. We observed higher Bdnf IV mRNA in high-intensity runners compared to controls, but no effects of acute exercise on memory. In the OFT, runners traveled less distance and spent more time grooming than controls. DSP-4 did not attenuate the effects of exercise. A single bout of exercise increases Bdnf IV mRNA in an intensity-dependent manner; however, high-intensity running reduces exploratory behavior in C57BL/6J mice.
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Affiliation(s)
- Andrew C Venezia
- Department of Exercise Science and Sport, The University of Scranton, Scranton, Pennsylvania
| | - Molly M Hyer
- Department of Psychology, University of Maryland, College Park, Maryland
| | - Erica R Glasper
- Department of Psychology, University of Maryland, College Park, Maryland
| | - Stephen M Roth
- Department of Kinesiology, School of Public Health, University of Maryland, College Park, Maryland
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Dong W, Cao Z, Pang Y, Feng T, Tian H. CARF, As An Oncogene, Promotes Colorectal Cancer Stemness By Activating ERBB Signaling Pathway. Onco Targets Ther 2019; 12:9041-9051. [PMID: 31802911 PMCID: PMC6830361 DOI: 10.2147/ott.s225733] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 10/14/2019] [Indexed: 12/27/2022] Open
Abstract
Introduction The role of CARF, a calcium-responsive transcription factor, in colorectal cancer initiation and development is still unknown. Here, we report that CARF promotes colorectal cancer stemness through ERBB signaling pathway. Materials and methods Both colorectal cancer cell lines and primary cells were used in this study. The levels of target mRNA and protein in the cells were examined by qRT-PCR and Western blot. Gene manipulation was achieved by the lentivirus delivery system. Luciferase reporter gene assay was employed to analyze the transcriptional activity of the promoter. ChIP assay was performed for the examination of the binding between CARF and the promoters of MAPK8 and JUN. Kaplan-Meier survival curve was generated by the R2 program. Correlation analysis was performed using Spearman correlation analysis. Results Aberrant upregulation of CARF has been found in tumor tissues of colorectal cancer patients and associated with poor prognosis. Ectopic expression of CARF promoted the sphere-formation activities, as well as the expression of stem cell markers in colorectal cancer cells and knockdown of CARF, inhibited these activities. The mechanistic analysis showed that CARF directly binds to the promoter of MAPK8 and JUN, promotes the expression of MAPK8 and JUN, activates the ERBB signaling pathway, and thereby promotes the maintenance of the stemness in colorectal cancer cells. Conclusion CARF, as an oncogene, promotes colorectal cancer stemness by activating ERBB signaling pathway. The ERBB signaling pathway that serves as the main downstream effector of CARF could be an efficient drug target for colorectal cancer caused by aberrant expression of CARF.
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Affiliation(s)
- Weiyi Dong
- Department of Pathology, Heze Municipal Hospital, Heze City, Shandong 274031, People's Republic of China
| | - Zheng Cao
- Department of Pathology, Juye County People's Hospital, Heze City, Shandong 274900, People's Republic of China
| | - Yanmin Pang
- Department of Intensive Care Unit, Heze Municipal Hospital, Heze City, Shandong 274031, People's Republic of China
| | - Teng Feng
- Department of Pathology, Heze Municipal Hospital, Heze City, Shandong 274031, People's Republic of China
| | - Hongtao Tian
- Department of Pathology, Heze Municipal Hospital, Heze City, Shandong 274031, People's Republic of China
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50
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Ong J, van den Berg A, Faiz A, Boudewijn IM, Timens W, Vermeulen CJ, Oliver BG, Kok K, Terpstra MM, van den Berge M, Brandsma CA, Kluiver J. Current Smoking is Associated with Decreased Expression of miR-335-5p in Parenchymal Lung Fibroblasts. Int J Mol Sci 2019; 20:ijms20205176. [PMID: 31635387 PMCID: PMC6829537 DOI: 10.3390/ijms20205176] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 09/22/2019] [Accepted: 10/16/2019] [Indexed: 02/07/2023] Open
Abstract
Cigarette smoking causes lung inflammation and tissue damage. Lung fibroblasts play a major role in tissue repair. Previous studies have reported smoking-associated changes in fibroblast responses and methylation patterns. Our aim was to identify the effect of current smoking on miRNA expression in primary lung fibroblasts. Small RNA sequencing was performed on lung fibroblasts from nine current and six ex-smokers with normal lung function. MiR-335-5p and miR-335-3p were significantly downregulated in lung fibroblasts from current compared to ex-smokers (false discovery rate (FDR) <0.05). Differential miR-335-5p expression was validated with RT-qPCR (p-value = 0.01). The results were validated in lung tissue from current and ex-smokers and in bronchial biopsies from non-diseased smokers and never-smokers (p-value <0.05). The methylation pattern of the miR-335 host gene, determined by methylation-specific qPCR, did not differ between current and ex-smokers. To obtain insights into the genes regulated by miR-335-5p in fibroblasts, we overlapped all proven miR-335-5p targets with our previously published miRNA targetome data in lung fibroblasts. This revealed Rb1, CARF, and SGK3 as likely targets of miR-335-5p in lung fibroblasts. Our study indicates that miR-335-5p downregulation due to current smoking may affect its function in lung fibroblasts by targeting Rb1, CARF and SGK3.
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Affiliation(s)
- Jennie Ong
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, 9713 GZ Groningen, The Netherlands.
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), 9713 GZ Groningen, The Netherlands.
| | - Anke van den Berg
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, 9713 GZ Groningen, The Netherlands.
| | - Alen Faiz
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), 9713 GZ Groningen, The Netherlands.
- University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, 9713 GZ Groningen, The Netherlands.
- University of Technology Sydney, Respiratory Bioinformatics and Molecular Biology (RBMB) Faculty of Science, Ultimo, NSW 2007, Australia.
| | - Ilse M Boudewijn
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), 9713 GZ Groningen, The Netherlands.
- University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, 9713 GZ Groningen, The Netherlands.
| | - Wim Timens
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, 9713 GZ Groningen, The Netherlands.
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), 9713 GZ Groningen, The Netherlands.
| | - Cornelis J Vermeulen
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), 9713 GZ Groningen, The Netherlands.
- University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, 9713 GZ Groningen, The Netherlands.
| | - Brian G Oliver
- Woolcock Institute of Medical Research, Respiratory Cellular and Molecular Biology, The University of Sydney, New South Wales 2037, Australia.
- University of Technology Sydney, School of Life Sciences, Sydney, New South Wales 2007, Australia.
| | - Klaas Kok
- University of Groningen, University Medical Center Groningen, Department of Genetics, 9713 GZ Groningen, The Netherlands.
| | - Martijn M Terpstra
- University of Groningen, University Medical Center Groningen, Department of Genetics, 9713 GZ Groningen, The Netherlands.
| | - Maarten van den Berge
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), 9713 GZ Groningen, The Netherlands.
- University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, 9713 GZ Groningen, The Netherlands.
| | - Corry-Anke Brandsma
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, 9713 GZ Groningen, The Netherlands.
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), 9713 GZ Groningen, The Netherlands.
| | - Joost Kluiver
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, 9713 GZ Groningen, The Netherlands.
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