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1
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Tao H, Wang C, Zou C, Zhu H, Zhang W. Unraveling the potential of neuroinflammation and autophagy in schizophrenia. Eur J Pharmacol 2025; 997:177469. [PMID: 40054715 DOI: 10.1016/j.ejphar.2025.177469] [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: 10/22/2024] [Revised: 02/03/2025] [Accepted: 03/04/2025] [Indexed: 03/17/2025]
Abstract
Schizophrenia (SCZ) is a complex and chronic psychiatric disorder that affects a significant proportion of the global population. Although the precise etiology of SCZ remains uncertain, recent studies have underscored the involvement of neuroinflammation and autophagy in its pathogenesis. Neuroinflammation, characterized by hyperactivated microglia and markedly elevated pro-inflammatory cytokines, has been observed in postmortem brain tissues of SCZ patients and is closely associated with disease severity. Autophagy, a cellular process responsible for eliminating damaged components and maintaining cellular homeostasis, is believed to play a pivotal role in neuronal health and the onset of SCZ. This review explores the roles and underlying mechanisms of neuroinflammation and autophagy in SCZ, with a particular focus on their intricate interplay. Additionally, we provide an overview of potential therapeutic strategies aimed at modulating neuroinflammation and autophagy, including nutritional interventions, anti-inflammatory drugs, antipsychotics, and plant-derived natural compounds. The review also addresses the dual effects of antipsychotics on autophagy. Our objective is to translate these insights into clinical practice, expanding the therapeutic options available to improve the overall health and well-being of individuals with SCZ.
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Affiliation(s)
- Hongxia Tao
- Mental Health Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Congyin Wang
- Department of Emergency Medicine, Chengdu Fifth People's Hospital, Chengdu, Sichuan, 611130, China
| | - Chuan Zou
- Department of General Practice, Chengdu Fifth People's Hospital, Chengdu, Sichuan, 611130, China
| | - Hongru Zhu
- Mental Health Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Wei Zhang
- Mental Health Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
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2
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Huang H, Luo Z, Min J, Luo W, Zhou X, Wang C. Targeting Neuroinflammation in Schizophrenia: A comprehensive review of mechanisms and pharmacological interventions. Int Immunopharmacol 2025; 159:114910. [PMID: 40424655 DOI: 10.1016/j.intimp.2025.114910] [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: 03/25/2025] [Revised: 05/15/2025] [Accepted: 05/17/2025] [Indexed: 05/29/2025]
Abstract
Schizophrenia is a complex psychiatric disorder traditionally linked to neurotransmitter imbalances, but growing evidence implicates neuroinflammation as a key factor in its pathogenesis. Core pathological features include aberrant microglial activation, elevated proinflammatory cytokines (e.g., IL-6, TNF-α), blood-brain barrier disruption, and oxidative stress, all contributing to neuronal dysfunction. Genetic, epigenetic, and neurodevelopmental abnormalities further intensify the link between neuroinflammation and clinical symptoms, including cognitive deficits and positive/negative symptoms. Therapeutically, anti-inflammatory strategies show promise: Non-steroidal anti-inflammatory drugs inhibit the cyclooxygenase pathway; minocycline modulates microglial activity; cytokine inhibitors regulate immune responses; and antioxidants and mitochondrial agents (e.g., N-acetylcysteine, omega-3 fatty acids) reduce oxidative damage. Emerging approaches such as cannabidiol and nanodelivery systems also demonstrate anti-inflammatory and neuroprotective potential. However, long-term safety, dosage optimization, and individual variability remain to be fully validated. Future research should integrate single-cell genomics, neuroimaging, and biomarker stratification to elucidate neuroinflammatory mechanisms and enable precise combination therapies. Combining immunomodulatory and neurotransmitter-based strategies may overcome the limitations of traditional antipsychotics and improve clinical outcomes.
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Affiliation(s)
- Hao Huang
- Department of General surgery, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
| | - Zijie Luo
- Department of Gastroenterology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang 441000, China
| | - Jieshu Min
- Department of Pharmacy, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang 441000, China
| | - Wenjie Luo
- School of Medicine and Health Management, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Xujia Zhou
- Department of Radiology, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
| | - Changxu Wang
- Department of Pharmacy, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China; School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China.
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3
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Huang Z, Ren Z, Wang S, Xiao L, Ling Y, Xie Y, Wang G, Zhou B. Urolithin A alleviates schizophrenic-like behaviors and cognitive impairment in rats through modulation of neuroinflammation, neurogenesis, and synaptic plasticity. Sci Rep 2025; 15:10477. [PMID: 40140679 PMCID: PMC11947095 DOI: 10.1038/s41598-025-93554-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
Cognitive impairment in schizophrenia occurs in the early stages of the disease and is closely associated with prognosis. Alleviation of cognitive impairment in schizophrenia faces major challenges owing to the lack of preventive and therapeutic drugs that are novel and effective. Urolithin A (UA) is a gut microbial metabolite of ellagic acid that has demonstrated neuroprotective effects in multiple neurological disease models. Nonetheless, the neuromodulatory role of UA in schizophrenia is yet to be elucidated. Wistar rat pups were separated from their mothers for 24 h on postnatal days (PNDs) 9-10 to establish an early-life stress model. The pups were pretreated with UA at different administration times (2, 4, and 6 weeks) and doses (50, 100, and 150 mg/kg) from adolescence (PND29). Behavioral tests were performed after the end of the administration. Subsequently, hippocampal samples were collected for histopathological and molecular evaluations. Male offspring rats subjected to maternal separation exhibited increased sensitivity to prepulse inhibition and cognitive impairment, accompanied by severe neuroinflammation and impaired neurogenesis. However, UA attenuated maternal separation-induced prepulse inhibition deficits and cognitive impairments and restored hippocampal neurogenesis in a dose-dependent manner. Furthermore, UA pretreatment preserved dendritic spine density, synapses, and presynaptic vesicles. In addition, it exerted anti-inflammatory effects by inhibiting microglial activation and expression of the proinflammatory cytokines tumor necrosis factor-α, interleukin-6, and interleukin-1β. Potential mechanisms included upregulation of brain-derived neurotrophic factor protein expression and activation of the extracellular signal-regulated kinase signaling pathway. This study is the first preclinical evaluation of the effects of UA on cognitive impairment in schizophrenia. The findings suggest that changes in cognitive function linked to schizophrenia are driven by the interaction among neuroinflammation, neurogenesis, and synaptic plasticity and that UA has the potential to reverse these processes. These observations provide evidence for future clinical trials of UA as a dietary supplement for preventing schizophrenia.
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Affiliation(s)
- Zhengyuan Huang
- Department of Psychiatry, Renmin Hospital of Wuhan University, Jiefang Road 238#, Wuhan, 430060, China
- Department of Pharmacy, Renmin Hospital of Wuhan University, Jiefang Road 238#, Wuhan, 430060, China
| | - Zhongyu Ren
- Department of Psychiatry, Renmin Hospital of Wuhan University, Jiefang Road 238#, Wuhan, 430060, China
| | - Sanwang Wang
- Department of Psychiatry, Renmin Hospital of Wuhan University, Jiefang Road 238#, Wuhan, 430060, China
| | - Ling Xiao
- Department of Psychiatry, Renmin Hospital of Wuhan University, Jiefang Road 238#, Wuhan, 430060, China
- Institute of Neuropsychiatry, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yipeng Ling
- Department of Pharmacy, Renmin Hospital of Wuhan University, Jiefang Road 238#, Wuhan, 430060, China
| | - Yinping Xie
- Department of Psychiatry, Renmin Hospital of Wuhan University, Jiefang Road 238#, Wuhan, 430060, China
- Institute of Neuropsychiatry, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Gaohua Wang
- Department of Psychiatry, Renmin Hospital of Wuhan University, Jiefang Road 238#, Wuhan, 430060, China.
- Institute of Neuropsychiatry, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
- Taikang Center for Life and Medical Sciences, Wuhan University, Donghu Road 115#, Wuhan, 430071, China.
| | - Benhong Zhou
- Department of Psychiatry, Renmin Hospital of Wuhan University, Jiefang Road 238#, Wuhan, 430060, China.
- Department of Pharmacy, Renmin Hospital of Wuhan University, Jiefang Road 238#, Wuhan, 430060, China.
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Mattei D, Guneykaya D, Ugursu B, Buonfiglioli A. From womb to world: The interplay between maternal immune activation, neuroglia, and neurodevelopment. HANDBOOK OF CLINICAL NEUROLOGY 2025; 210:269-285. [PMID: 40148048 DOI: 10.1016/b978-0-443-19102-2.00028-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
This chapter introduces and discusses maternal immune activation (MIA) as a contributing factor in increasing the risk of neurodevelopmental disorders, particularly in relation to its interactions with neuroglia. Here we first provide an overview of the neuroglia-astroglia, oligodendroglia, microglia, and radial glial cells-and their important role during early brain development and in adulthood. We then present and discuss MIA, followed by a critical overview of inflammatory molecules and temporal stages associated to maternal inflammation during pregnancy. We provide an overview of animal and human models used to mimic and study MIA. Furthermore, we review the possible interaction between MIA and neuroglia, focusing on the current advances in both modeling and therapeutics. Additionally, we discuss and provide preliminary and interesting insights into the most recent pandemic, COVID-19, and how the infection may be associated to MIA and increased risk for neurodevelopmental disorders. Finally, we provide a critical overview of challenges and future opportunities to study how MIA may contribute to higher risk of developing neurodevelopmental disorders.
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Affiliation(s)
- Daniele Mattei
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, Friedman Brain Institute, New York, NY, United States
| | - Dilansu Guneykaya
- Department of Neurobiology, Harvard Medical School, Boston, MA, United States
| | - Bilge Ugursu
- Department of Psychoneuroimmunology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Alice Buonfiglioli
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
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Buonfiglioli A, Kübler R, Missall R, De Jong R, Chan S, Haage V, Wendt S, Lin AJ, Mattei D, Graziani M, Latour B, Gigase F, Chiu R, Zhang Y, Nygaard HB, De Jager PL, De Witte LD. A microglia-containing cerebral organoid model to study early life immune challenges. Brain Behav Immun 2025; 123:1127-1146. [PMID: 39500415 PMCID: PMC11753195 DOI: 10.1016/j.bbi.2024.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 10/10/2024] [Accepted: 11/02/2024] [Indexed: 11/13/2024] Open
Abstract
Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs. How the maternal as well as the fetal immune system affect human neurodevelopment and contribute to NDDs remains unclear. An important reason for this knowledge gap is the fact that the impact of exposure to prenatal risk factors has been challenging to study in the human context. Here, we characterized a model of cerebral organoids (CO) with integrated microglia (COiMg). These organoids express typical microglial markers and respond to inflammatory stimuli. The presence of microglia influences cerebral organoid development, including cell density and neural differentiation, and regulates the expression of several ciliated and mesenchymal cell markers. Moreover, COiMg and organoids without microglia show similar but also distinct responses to inflammatory stimuli. Additionally, IFN-γ induced significant transcriptional and structural changes in the cerebral organoids, that appear to be regulated by the presence of microglia. Specifically, interferon-gamma (IFN-γ) was found to alter the expression of genes linked to autism. This model provides a valuable tool to study how inflammatory perturbations and microglial presence affect neurodevelopmental processes.
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Affiliation(s)
- Alice Buonfiglioli
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Raphael Kübler
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Human Genetics, Radboud UMC, Nijmegen, Netherlands (the)
| | - Roy Missall
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Renske De Jong
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Stephanie Chan
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Verena Haage
- Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
| | - Stefan Wendt
- Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver V6T 1Z3, Canada
| | - Ada J Lin
- Division of Neurology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver V6T 1Z3, Canada
| | - Daniele Mattei
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mara Graziani
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Human Genetics, Radboud UMC, Nijmegen, Netherlands (the); Donders Institute for Brain, Cognition and Behaviour, 6500 HB, Nijmegen, Netherlands (the)
| | - Brooke Latour
- Department of Human Genetics, Radboud UMC, Nijmegen, Netherlands (the); Donders Institute for Brain, Cognition and Behaviour, 6500 HB, Nijmegen, Netherlands (the)
| | - Frederieke Gigase
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Rebecca Chiu
- Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
| | - Ya Zhang
- Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
| | - Haakon B Nygaard
- Division of Neurology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver V6T 1Z3, Canada
| | - Philip L De Jager
- Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
| | - Lot D De Witte
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Human Genetics, Radboud UMC, Nijmegen, Netherlands (the); Donders Institute for Brain, Cognition and Behaviour, 6500 HB, Nijmegen, Netherlands (the); Department of Psychiatry, Radboud UMC, Nijmegen, Netherlands (the)
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6
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Guma E, Chakravarty MM. Immune Alterations in the Intrauterine Environment Shape Offspring Brain Development in a Sex-Specific Manner. Biol Psychiatry 2025; 97:12-27. [PMID: 38679357 PMCID: PMC11511788 DOI: 10.1016/j.biopsych.2024.04.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 03/20/2024] [Accepted: 04/17/2024] [Indexed: 05/01/2024]
Abstract
Exposure to immune dysregulation in utero or in early life has been shown to increase risk for neuropsychiatric illness. The sources of inflammation can be varied, including acute exposures due to maternal infection or acute stress, or persistent exposures due to chronic stress, obesity, malnutrition, or autoimmune diseases. These exposures may cause subtle alteration in brain development, structure, and function that can become progressively magnified across the lifespan, potentially increasing the likelihood of developing a neuropsychiatric conditions. There is some evidence that males are more susceptible to early-life inflammatory challenges than females. In this review, we discuss the various sources of in utero or early-life immune alteration and the known effects on fetal development with a sex-specific lens. To do so, we leveraged neuroimaging, behavioral, cellular, and neurochemical findings. Gaining clarity about how the intrauterine environment affects offspring development is critically important for informing preventive and early intervention measures that may buffer against the effects of these early-life risk factors.
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Affiliation(s)
- Elisa Guma
- Section on Developmental Neurogenomics, Human Genetics Branch, National Institute of Mental Health, Bethesda, Maryland; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
| | - M Mallar Chakravarty
- Computational Brain Anatomy Laboratory, Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal, Quebec, Canada; Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal, Quebec, Canada; Department of Psychiatry, McGill University, Montreal, Quebec, Canada; Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada
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7
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Sonego AB, Prado DS, Uliana DL, Cunha TM, Grace AA, Resstel LBM. Pioglitazone attenuates behavioral and electrophysiological dysfunctions induced by two-hit model of schizophrenia in adult rodent offspring. Eur Neuropsychopharmacol 2024; 89:28-40. [PMID: 39332147 PMCID: PMC11606766 DOI: 10.1016/j.euroneuro.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 08/27/2024] [Accepted: 09/01/2024] [Indexed: 09/29/2024]
Abstract
Maternal infection and stress exposure, especially during childhood and adolescence, have been implicated as risk factors for schizophrenia. Both insults induce an exacerbated inflammatory response, which could mediate disturbance of neurodevelopmental processes and, ultimately, malfunctioning of neural systems observed in this disorder. Thus, anti-inflammatory drugs, such as PPARγ agonists, may potentially be used to prevent the development of schizophrenia. Microglia culture was prepared from the offspring of saline or poly(I:C)-injected mice. The cells were pretreated with pioglitazone and then, stimulated by LPS. Proinflammatory mediators and phagocytic activity were measured. Also, pregnant rats were injected with saline or poly(I:C) on GD17. The offspring were subjected to footshock during adolescence and subsequently injected with pioglitazone or vehicle. At adulthood, behavior and dopaminergic activity were evaluated. Pioglitazone reduced proinflammatory mediators induced by poly(I:C) microglia stimulated by LPS without affecting their decreased phagocytic activity. The PPARγ agonist also prevented the emergence of social and cognitive impairments, as well as attenuated the increased number of spontaneously active dopamine neurons in the VTA, observed in both males and females from poly(I:C) and stress group. Therefore, pioglitazone could potentially prevent the emergence of the schizophrenia-like alterations induced by the two-hit model via reduction of microglial activation.
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Affiliation(s)
- Andreza B Sonego
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, 14049-900, Ribeirão Preto, SP, Brazil; Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, A210 Langley Hall, 15260, Pittsburgh, PA, USA.
| | - Douglas S Prado
- Department of Immunology, University of Pittsburgh, The Assembly Building, 15213, Pittsburgh, PA, USA
| | - Daniela L Uliana
- Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, A210 Langley Hall, 15260, Pittsburgh, PA, USA
| | - Thiago M Cunha
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, 14049-900, Ribeirão Preto, SP, Brazil
| | - Anthony A Grace
- Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, A210 Langley Hall, 15260, Pittsburgh, PA, USA
| | - Leonardo B M Resstel
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, 14049-900, Ribeirão Preto, SP, Brazil
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Chen T, Meng H, Fang N, Shi P, Chen M, Liu Q, Lv L, Li W. Age-related changes in behavior profile in male offspring of rats treated with poly I:C-induced maternal immune activation in early gestation. Animal Model Exp Med 2024; 7:914-925. [PMID: 38741390 PMCID: PMC11680485 DOI: 10.1002/ame2.12417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 03/21/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Autism and schizophrenia are environmental risk factors associated with prenatal viral infection during pregnancy. It is still unclear whether behavior phenotypes change at different developmental stages in offspring following the activation of the maternal immune system. METHODS Sprague-Dawley rats received a single caudal vein injection of 10 mg/kg polyinosinic:polycytidylic acid (poly I:C) on gestational day 9 and the offspring were comprehensively tested for behaviors in adolescence and adulthood. RESULTS Maternal serum levels of interleukin (IL)-6, IL-1β and tumor necrosis factor-α were elevated in poly I:C-treated dams. The offspring of maternal poly I:C-induced rats showed increased anxiety, impaired social approach, and progressive impaired cognitive and sensorimotor gating function. CONCLUSION Maternal immune activation led to developmental specificity behavioral impairment in offspring.
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Affiliation(s)
- Tengfei Chen
- Henan Mental HospitalThe Second Affiliated Hospital of Xinxiang Medical UniversityXinxiangChina
- Henan Key Lab of Biological Psychiatry of Xinxiang Medical UniversityXinxiangChina
- International Joint Research Laboratory for Psychiatry and Neuroscience of HenanXinxiangChina
| | - Huadan Meng
- Henan Mental HospitalThe Second Affiliated Hospital of Xinxiang Medical UniversityXinxiangChina
- Henan Key Lab of Biological Psychiatry of Xinxiang Medical UniversityXinxiangChina
- International Joint Research Laboratory for Psychiatry and Neuroscience of HenanXinxiangChina
| | - Ni Fang
- Henan Mental HospitalThe Second Affiliated Hospital of Xinxiang Medical UniversityXinxiangChina
- Henan Key Lab of Biological Psychiatry of Xinxiang Medical UniversityXinxiangChina
- International Joint Research Laboratory for Psychiatry and Neuroscience of HenanXinxiangChina
| | - Peiling Shi
- Henan Mental HospitalThe Second Affiliated Hospital of Xinxiang Medical UniversityXinxiangChina
- Henan Key Lab of Biological Psychiatry of Xinxiang Medical UniversityXinxiangChina
- International Joint Research Laboratory for Psychiatry and Neuroscience of HenanXinxiangChina
| | - Mengxue Chen
- Henan Mental HospitalThe Second Affiliated Hospital of Xinxiang Medical UniversityXinxiangChina
- Henan Key Lab of Biological Psychiatry of Xinxiang Medical UniversityXinxiangChina
- International Joint Research Laboratory for Psychiatry and Neuroscience of HenanXinxiangChina
| | - Qing Liu
- Henan Mental HospitalThe Second Affiliated Hospital of Xinxiang Medical UniversityXinxiangChina
- Henan Key Lab of Biological Psychiatry of Xinxiang Medical UniversityXinxiangChina
- International Joint Research Laboratory for Psychiatry and Neuroscience of HenanXinxiangChina
| | - Luxian Lv
- Henan Mental HospitalThe Second Affiliated Hospital of Xinxiang Medical UniversityXinxiangChina
- Henan Key Lab of Biological Psychiatry of Xinxiang Medical UniversityXinxiangChina
- International Joint Research Laboratory for Psychiatry and Neuroscience of HenanXinxiangChina
- Henan Province People's HospitalZhengzhouHenanChina
| | - Wenqiang Li
- Henan Mental HospitalThe Second Affiliated Hospital of Xinxiang Medical UniversityXinxiangChina
- Henan Key Lab of Biological Psychiatry of Xinxiang Medical UniversityXinxiangChina
- International Joint Research Laboratory for Psychiatry and Neuroscience of HenanXinxiangChina
- Henan Collaborative Innovation Center of Prevention and Treatment of Mental DisorderXinxiang Medical UniversityXinxiangChina
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9
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DeVeaux SA, Vyshnya S, Propsom K, Gbotosho OT, Singh AS, Horning RZ, Sharma M, Jegga AG, Niu L, Botchwey EA, Hyacinth HI. Neuroinflammation underlies the development of social stress induced cognitive deficit in male sickle cell mice. Exp Biol Med (Maywood) 2024; 249:10361. [PMID: 39629138 PMCID: PMC11612828 DOI: 10.3389/ebm.2024.10361] [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: 09/01/2024] [Accepted: 10/17/2024] [Indexed: 12/06/2024] Open
Abstract
Cognitive deficit is a debilitating complication of sickle cell disease (SCD), with a multifactorial etiopathogenesis. Here we show that neuroinflammation and dysregulation in lipidomics and transcriptomics profiles are major underlying mechanisms of social stress-induced cognitive deficit in SCD. Male Townes sickle cell (SS) mice and controls (AA) were exposed to social stress using the repeat social defeat (RSD) paradigm concurrently with or without treatment with minocycline. Mice were tested for cognitive deficit using novel object recognition and fear conditioning tests. SS mice exposed to RSD without treatment had worse performance on cognitive tests compared to SS mice exposed to RSD with treatment or to AA controls, irrespective of their RSD or treatment disposition. Additionally, compared to SS mice exposed to RSD with treatment, SS mice exposed to RSD without treatment had significantly more cellular evidence of neuroinflammation coupled with a significant shift in the differentiation of neural progenitor cells towards astrogliogenesis. Additionally, brain tissue from SS mice exposed to RSD was significantly enriched for genes associated with blood-brain barrier dysfunction, neuron excitotoxicity, inflammation, and significant dysregulation in sphingolipids important to neuronal cell processes. We demonstrate in this study that social stress induces cognitive deficit in SS mice, concurrently with neuroinflammation and lipid dysregulation.
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Affiliation(s)
- S’Dravious A. DeVeaux
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory, Atlanta, GA, United States
- Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, United States
| | - Sofiya Vyshnya
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory, Atlanta, GA, United States
- Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, United States
| | - Katherine Propsom
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Oluwabukola T. Gbotosho
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Asem S. Singh
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Robert Z. Horning
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Mihika Sharma
- Division of Biomedical Informatics, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine Cincinnati, Cincinnati, OH, United States
| | - Anil G. Jegga
- Division of Biomedical Informatics, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine Cincinnati, Cincinnati, OH, United States
| | - Liang Niu
- Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Edward A. Botchwey
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory, Atlanta, GA, United States
- Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, United States
| | - Hyacinth I. Hyacinth
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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10
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Smail MA, Lenz KM. Developmental functions of microglia: Impact of psychosocial and physiological early life stress. Neuropharmacology 2024; 258:110084. [PMID: 39025401 PMCID: PMC12051134 DOI: 10.1016/j.neuropharm.2024.110084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 07/03/2024] [Accepted: 07/15/2024] [Indexed: 07/20/2024]
Abstract
Microglia play numerous important roles in brain development. From early embryonic stages through adolescence, these immune cells influence neuronal genesis and maturation, guide connectivity, and shape brain circuits. They also interact with other glial cells and structures, influencing the brain's supportive microenvironment. While this central role makes microglia essential, it means that early life perturbations to microglia can have widespread effects on brain development, potentially resulting in long-lasting behavioral impairments. Here, we will focus on the effects of early life psychosocial versus physiological stressors in rodent models. Psychosocial stress refers to perceived threats that lead to stress axes activation, including prenatal stress, or chronic postnatal stress, including maternal separation and resource scarcity. Physiological stress refers to physical threats, including maternal immune activation, postnatal infection, and traumatic brain injury. Differing sources of early life stress have varied impacts on microglia, and these effects are moderated by factors such as developmental age, brain region, and sex. Overall, these stressors appear to either 1) upregulate basal microglia numbers and activity throughout the lifespan, while possibly blunting their responsivity to subsequent stressors, or 2) shift the developmental curve of microglia, resulting in differential timing and function, impacting the critical periods they govern. Either could contribute to behavioral dysfunctions that occur after the resolution of early life stress. Exploring how different stressors impact microglia, as well as how multiple stressors interact to alter microglia's developmental functions, could deepen our understanding of how early life stress changes the brain's developmental trajectory. This article is part of the Special Issue on "Microglia".
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Affiliation(s)
- Marissa A Smail
- Department of Psychology, Ohio State University, Columbus, OH, USA.
| | - Kathryn M Lenz
- Department of Psychology, Ohio State University, Columbus, OH, USA; Department of Neuroscience, Ohio State University, Columbus, OH, USA; Institute for Behavioral Medicine Research, Ohio State University, Columbus, OH, USA; Chronic Brain Injury Program, Ohio State University, Columbus, OH, USA
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11
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Zeng X, Fan L, Qin Q, Zheng D, Wang H, Li M, Jiang Y, Wang H, Liu H, Liang S, Wu L, Liang S. Exogenous PD-L1 binds to PD-1 to alleviate and prevent autism-like behaviors in maternal immune activation-induced male offspring mice. Brain Behav Immun 2024; 122:527-546. [PMID: 39182588 DOI: 10.1016/j.bbi.2024.08.042] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 08/15/2024] [Accepted: 08/22/2024] [Indexed: 08/27/2024] Open
Abstract
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder caused by the interaction of multiple pathogenic factors. Epidemiological studies and animal experiments indicate that maternal immune activation (MIA) is closely related to the development of ASD in offspring. A large number of pro-inflammatory cytokines are transferred from the placenta to the fetal brain during MIA, which impedes fetal neurodevelopment and is accompanied by activation of immune cells and microglia. Programmed cell death protein 1 (PD-1) can be highly expressed on the surface of various activated immune cells, when combined with programmed cell death-ligand 1 (PD-L1), it can activate the PD-1/PD-L1 pathway and exert powerful immunosuppressive effects, suggesting that this immune checkpoint may have the potential to treat MIA-induced ASD. This study combined bioinformatics analysis and experimental validation to explore the efficacy of Fc-fused PD-L1 (PD-L1-Fc) in treating MIA-induced ASD. Bioinformatics analysis results showed that in human placental inflammation, IL-6 was upregulated, T cells proliferated significantly, and the PD-1/PD-L1 pathway was significantly enriched. The experimental results showed that intraperitoneal injection of poly(I:C) induced MIA in pregnant mice resulted in significant expression of IL-6 in their serum, placenta, and fetal brain. At the same time, the expression of PD-1 and PD-L1 in the placenta and fetal brain increased, CD4+ T cells in the spleen were significantly activated, and PD-1 expression increased. Their offspring mice exhibited typical ASD-like behaviors. In vitro experiments on primary microglia of offspring mice have confirmed that the expression of IL-6, PD-1, and PD-L1 is significantly increased, and PD-L1-Fc effectively reduced their expression levels. In the prefrontal cortex of MIA offspring mice, there was an increase in the expression of IL-6, PD-1, and PD-L1; activation of microglial cells, and colocalization with PD-1. Then we administered brain stereotaxic injections of PD-L1-Fc to MIA offspring mice and intraperitoneal injections to MIA pregnant mice. The results indicated that PD-L1-Fc effectively suppressed neuroinflammation in the frontal cortex of offspring mice and partially ameliorated ASD-like behaviors; MIA in pregnant mice was significantly alleviated, and the offspring mice they produced did not exhibit neuroinflammation or ASD-like behaviors. In summary, we have demonstrated the therapeutic ability of PD-L1-Fc for MIA-induced ASD, aiming to provide new strategies and insights for the treatment of ASD.
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Affiliation(s)
- Xin Zeng
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Linlin Fan
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Qian Qin
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Danyang Zheng
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Han Wang
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Mengyue Li
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Yutong Jiang
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Hui Wang
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Hao Liu
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Shengjun Liang
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Lijie Wu
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China.
| | - Shuang Liang
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China.
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12
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Gillespie B, Dunn A, Sundram S, Hill RA. Investigating 7,8-Dihydroxyflavone to combat maternal immune activation effects on offspring gene expression and behaviour. Prog Neuropsychopharmacol Biol Psychiatry 2024; 134:111078. [PMID: 38950841 DOI: 10.1016/j.pnpbp.2024.111078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/03/2024]
Abstract
Infection during pregnancy is a substantial risk factor for the unborn child to develop autism or schizophrenia later in life, and is thought to be driven by maternal immune activation (MIA). MIA can be modelled by exposing pregnant mice to Polyinosinic: polycytidylic acid (Poly-I:C), a viral mimetic that induces an immune response and recapitulates in the offspring many neurochemical features of ASD and schizophrenia, including altered BDNF-TrkB signalling and disruptions to excitatory/inhibitory balance. Therefore, we hypothesised that a BDNF mimetic, 7,8-Dihydroxyflavone (7,8-DHF), administered prophylactically to the dam may prevent the neurobehavioural sequelae of disruptions induced by MIA. Dams were treated with 7,8-DHF in the drinking water (0.08 mg/ML) from gestational day (GD) 9-20 and were exposed to Poly-I:C at GD17 (20 mg/kg, i.p.). Foetal brains were collected 6 h post Poly-I:C exposure for RT-qPCR analysis of BDNF, cytokine, GABAergic and glutamatergic gene targets. A second adult cohort were tested in a battery of behavioural tests relevant to schizophrenia and the prefrontal cortex and ventral hippocampus dissected for RT-qPCR analysis. Foetal brains exposed to Poly-I:C showed increased IL-6, but reduced expression of Ntrk2 and multiple GABAergic and glutamatergic markers. Anxiety-like behaviour was observed in adult offspring prenatally exposed to poly-I:C, which was accompanied by altered expression of Gria2 in the prefrontal cortex and Gria4 in the ventral hippocampus. While 7-8 DHF normalised the expression of some glutamatergic (Grm5) and GABAergic (Gabra1) genes in Poly-I:C exposed offspring, it also led to substantial alterations in offspring not exposed to Poly-I:C. Furthermore, mice exposed to 7,8-DHF prenatally showed increased pre-pulse inhibition and reduced working memory in adulthood. These data advance understanding of how 7,8-DHF and MIA prenatal exposure impacts genes critical to excitatory/inhibitory pathways and related behaviour.
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Affiliation(s)
- Brendan Gillespie
- Department of Psychiatry, Monash University, Clayton, VIC 3168, Australia
| | - Ariel Dunn
- Department of Psychiatry, Monash University, Clayton, VIC 3168, Australia
| | - Suresh Sundram
- Department of Psychiatry, Monash University, Clayton, VIC 3168, Australia
| | - Rachel A Hill
- Department of Psychiatry, Monash University, Clayton, VIC 3168, Australia.
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13
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Khan MM, Khan ZA, Khan MA. Metabolic complications of psychotropic medications in psychiatric disorders: Emerging role of de novo lipogenesis and therapeutic consideration. World J Psychiatry 2024; 14:767-783. [PMID: 38984346 PMCID: PMC11230099 DOI: 10.5498/wjp.v14.i6.767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 05/05/2024] [Accepted: 05/23/2024] [Indexed: 06/19/2024] Open
Abstract
Although significant advances have been made in understanding the patho-physiology of psychiatric disorders (PDs), therapeutic advances have not been very convincing. While psychotropic medications can reduce classical symptoms in patients with PDs, their long-term use has been reported to induce or exaggerate various pre-existing metabolic abnormalities including diabetes, obesity and non-alcoholic fatty liver disease (NAFLD). The mechanism(s) underlying these metabolic abnormalities is not clear; however, lipid/fatty acid accumulation due to enhanced de novo lipogenesis (DNL) has been shown to reduce membrane fluidity, increase oxidative stress and inflammation leading to the development of the aforementioned metabolic abnormalities. Intriguingly, emerging evidence suggest that DNL dysregulation and fatty acid accumulation could be the major mechanisms associated with the development of obesity, diabetes and NAFLD after long-term treatment with psychotropic medications in patients with PDs. In support of this, several adjunctive drugs comprising of anti-oxidants and anti-inflammatory agents, that are used in treating PDs in combination with psychotropic medications, have been shown to reduce insulin resistance and development of NAFLD. In conclusion, the above evidence suggests that DNL could be a potential pathological factor associated with various metabolic abnormalities, and a new avenue for translational research and therapeutic drug designing in PDs.
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Affiliation(s)
- Mohammad M Khan
- Laboratory of Translational Neurology and Molecular Psychiatry, Department of Biotechnology, Era’s Lucknow Medical College and Hospital, and Faculty of Science, Era University, Lucknow 226003, India
| | - Zaw Ali Khan
- Era’s Lucknow Medical College and Hospital, Era University, Lucknow 226003, India
| | - Mohsin Ali Khan
- Era’s Lucknow Medical College and Hospital, Era University, Lucknow 226003, India
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14
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Buonfiglioli A, Kübler R, Missall R, De Jong R, Chan S, Haage V, Wendt S, Lin AJ, Mattei D, Graziani M, Latour B, Gigase F, Nygaard HB, De Jager PL, De Witte LD. A microglia-containing cerebral organoid model to study early life immune challenges. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.24.595814. [PMID: 38826204 PMCID: PMC11142229 DOI: 10.1101/2024.05.24.595814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs. How the maternal as well as the fetal immune system affect human neurodevelopment and contribute to NDDs remains unclear. An important reason for this knowledge gap is the fact that the impact of exposure to prenatal risk factors has been challenging to study in the human context. Here, we characterized a model of cerebral organoids (CO) with integrated microglia (COiMg). These organoids express typical microglial markers and respond to inflammatory stimuli. The presence of microglia influences cerebral organoid development, including cell density and neural differentiation, and regulates the expression of several ciliated mesenchymal cell markers. Moreover, COiMg and organoids without microglia show similar but also distinct responses to inflammatory stimuli. Additionally, IFN-γ induced significant transcriptional and structural changes in the cerebral organoids, that appear to be regulated by the presence of microglia. Specifically, interferon-gamma (IFN-γ) was found to alter the expression of genes linked to autism. This model provides a valuable tool to study how inflammatory perturbations and microglial presence affect neurodevelopmental processes.
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Affiliation(s)
- Alice Buonfiglioli
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Raphael Kübler
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Human Genetics, Radboud UMC, Nijmegen, The Netherlands
| | - Roy Missall
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Renske De Jong
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Stephanie Chan
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Verena Haage
- Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
| | - Stefan Wendt
- Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, V6T 1Z3, Canada
| | - Ada J. Lin
- Division of Neurology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, V6T 1Z3, Canada
| | - Daniele Mattei
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mara Graziani
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Human Genetics, Radboud UMC, Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, 6500 HB, Nijmegen, The Netherlands
| | - Brooke Latour
- Department of Human Genetics, Radboud UMC, Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, 6500 HB, Nijmegen, The Netherlands
| | - Frederieke Gigase
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Haakon B. Nygaard
- Division of Neurology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, V6T 1Z3, Canada
| | - Philip L. De Jager
- Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
| | - Lot D. De Witte
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Human Genetics, Radboud UMC, Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, 6500 HB, Nijmegen, The Netherlands
- Department of Psychiatry, Radboud UMC, Nijmegen, The Netherlands
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15
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Rezaei A, Moqadami A, Khalaj-Kondori M. Minocycline as a prospective therapeutic agent for cancer and non-cancer diseases: a scoping review. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:2835-2848. [PMID: 37991540 DOI: 10.1007/s00210-023-02839-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 11/05/2023] [Indexed: 11/23/2023]
Abstract
Minocycline is an FDA-approved secondary-generation tetracycline antibiotic. It is a synthetic antibiotic having many biological effects, such as antioxidant, anti-inflammatory, anti-cancer, and neuroprotective functions. This study discusses the pharmacological mechanisms of preventive and therapeutic effects of minocycline. Specifically, it provides a comprehensive overview of the molecular pathways by which minocycline acts on the different cancers, including ovarian, breast, glioma, colorectal, liver, pancreatic, lung, prostate, melanoma, head and neck, leukemia, and non-cancer diseases such as Alzheimer's disease, Parkinson, schizophrenia, multiple sclerosis, Huntington, polycystic ovary syndrome, and coronavirus disease 19. Minocycline may be a potential medication for these disorders due to its strong blood-brain barrier penetrance. It is also widely accepted as a specific medication, has a well-known side-effect characteristic, is reasonably priced, making it appropriate for continuous use in managing diseases, and has been demonstrated as an oral approach because it is effectively absorbed and accomplished almost all of the body's parts.
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Affiliation(s)
- Abedeh Rezaei
- Department of Animal Biology¸ Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Amin Moqadami
- Department of Animal Biology¸ Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Mohammad Khalaj-Kondori
- Department of Animal Biology¸ Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
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16
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Abbasi H, Ghavami-Kia S, Davoodian N, Davoodian N. Maternal quercetin supplementation improved lipopolysaccharide-induced cognitive deficits and inflammatory response in a rat model of maternal immune activation. Toxicol Appl Pharmacol 2024; 483:116830. [PMID: 38246289 DOI: 10.1016/j.taap.2024.116830] [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: 10/24/2023] [Revised: 12/27/2023] [Accepted: 01/18/2024] [Indexed: 01/23/2024]
Abstract
BACKGROUND There is strong evidence that prenatal infection during a specific period of brain development increases the risk of neurodevelopmental disorders, partly through immune-inflammatory pathways. This suggests that anti-inflammatory agents could prevent these disorders by targeting the maternal inflammatory response. In the present study, we used a rat model of maternal immune activation (MIA) to examine whether maternal quercetin (QE) supplementation can alleviate behavioral deficits and inflammatory mediators in the prefrontal cortex (PFC) and hippocampus of adult male offspring. METHODS Pregnant rats were supplemented with QE (50 mg/kg) or vehicle throughout pregnancy and injected with either lipopolysaccharide (0.5 mg/kg) or saline on gestational days 15/16. At postnatal day 60, we evaluated the offspring's behavior, hippocampal and prefrontal cortex glial density, pro-inflammatory gene expression, and neuronal survival. RESULTS Our data showed that maternal QE supplementation can prevent working and recognition memory impairments in adult MIA offspring. This behavioral improvement correlates with the decrease in MIA-induced expression of pro-inflammatory genes, microglia, and astrocyte densities, without affecting neuronal survival, in both PFC and CA1 hippocampus areas. CONCLUSION Therefore, our study supports the potential preventive effect of QE on MIA-induced behavioral dysfunctions, at least in part, by suppressing the glial-mediated inflammatory response.
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Affiliation(s)
- Hossein Abbasi
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Sina Ghavami-Kia
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Nahid Davoodian
- Endocrinology and Metabolism Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
| | - Najmeh Davoodian
- Research Institute of Animal Embryo Technology, Shahrekord University, Shahrekord, Iran
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DeVeaux SA, Vyshnya S, Propsom K, Gbotosho OT, Singh AS, Horning RZ, Sharma M, Jegga AG, Niu L, Botchwey EA, Hyacinth HI. Neuroinflammation underlies the development of social stress induced cognitive deficit in sickle cell disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.24.577074. [PMID: 38328164 PMCID: PMC10849745 DOI: 10.1101/2024.01.24.577074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Cognitive deficit is a debilitating complication of SCD with multifactorial pathobiology. Here we show that neuroinflammation and dysregulation in lipidomics and transcriptomics profiles are major underlying mechanisms of social stress-induced cognitive deficit in SCD. Townes sickle cell (SS) mice and controls (AA) were exposed to social stress using the repeat social defeat (RSD) paradigm concurrently with or without treatment with minocycline. Mice were tested for cognitive deficit using novel object recognition (NOR) and fear conditioning (FC) tests. SS mice exposed to RSD without treatment had worse performance on cognitive tests compared to SS mice exposed to RSD with treatment or to AA controls, irrespective of their RSD or treatment disposition. Additionally, compared to SS mice exposed to RSD with treatment, SS mice exposed to RSD without treatment had significantly more cellular evidence of neuroinflammation coupled with a significant shift in the differentiation of neural progenitor cells towards astrogliogenesis. Additionally, brain tissue from SS mice exposed to RSD was significantly enriched for genes associated with blood-brain barrier dysfunction, neuron excitotoxicity, inflammation, and significant dysregulation in sphingolipids important to neuronal cell processes. We demonstrate in this study that neuroinflammation and lipid dysregulation are potential underlying mechanisms of social stress-related cognitive deficit in SS mice.
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Affiliation(s)
- S’Dravious A. DeVeaux
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory, Atlanta, GA, USA
- Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA
| | - Sofiya Vyshnya
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory, Atlanta, GA, USA
- Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA
| | - Katherine Propsom
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Oluwabukola T. Gbotosho
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Asem S. Singh
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Robert Z. Horning
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Mihika Sharma
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine Cincinnati, OH, USA
| | - Anil G. Jegga
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine Cincinnati, OH, USA
| | - Liang Niu
- Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Edward A. Botchwey
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory, Atlanta, GA, USA
- Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA
| | - Hyacinth I. Hyacinth
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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18
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Breach MR, Akouri HE, Costantine S, Dodson CM, McGovern N, Lenz KM. Prenatal allergic inflammation in rats confers sex-specific alterations to oxytocin and vasopressin innervation in social brain regions. Horm Behav 2024; 157:105427. [PMID: 37743114 PMCID: PMC10842952 DOI: 10.1016/j.yhbeh.2023.105427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 08/30/2023] [Accepted: 09/12/2023] [Indexed: 09/26/2023]
Abstract
Prenatal exposure to inflammation via maternal infection, allergy, or autoimmunity increases one's risk for developing neurodevelopmental and psychiatric disorders. Many of these disorders are associated with altered social behavior, yet the mechanisms underlying inflammation-induced social impairment remain unknown. We previously found that a rat model of acute allergic maternal immune activation (MIA) produced deficits like those found in MIA-linked disorders, including impairments in juvenile social play behavior. The neuropeptides oxytocin (OT) and arginine vasopressin (AVP) regulate social behavior, including juvenile social play, across mammalian species. OT and AVP are also implicated in neuropsychiatric disorders characterized by social impairment, making them good candidate regulators of social deficits after MIA. We profiled how acute prenatal exposure to allergic MIA changed OT and AVP innervation in several brain regions important for social behavior in juvenile male and female rat offspring. We also assessed whether MIA altered additional behavioral phenotypes related to sociality and anxiety. We found that allergic MIA increased OT and AVP fiber immunoreactivity in the medial amygdala and had sex-specific effects in the nucleus accumbens, bed nucleus of the stria terminalis, and lateral hypothalamic area. We also found that MIA reduced ultrasonic vocalizations in neonates and increased the stereotypical nature of self-grooming behavior. Overall, these findings suggest that there may be sex-specific mechanisms underlying MIA-induced behavioral impairment and underscore OT and AVP as ideal candidates for future mechanistic studies.
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Affiliation(s)
- Michaela R Breach
- Neuroscience Graduate Program, The Ohio State University, Columbus, OH, USA
| | - Habib E Akouri
- Department of Psychology, The Ohio State University, Columbus, OH, USA
| | - Sophia Costantine
- Department of Neuroscience, The Ohio State University, Columbus, OH, USA
| | - Claire M Dodson
- Department of Psychology, The Ohio State University, Columbus, OH, USA
| | - Nolan McGovern
- Department of Psychology, The Ohio State University, Columbus, OH, USA
| | - Kathryn M Lenz
- Department of Psychology, The Ohio State University, Columbus, OH, USA; Department of Neuroscience, The Ohio State University, Columbus, OH, USA; Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, USA.
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19
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Luo Y, Lv K, Du Z, Zhang D, Chen M, Luo J, Wang L, Liu T, Gong H, Fan X. Minocycline improves autism-related behaviors by modulating microglia polarization in a mouse model of autism. Int Immunopharmacol 2023; 122:110594. [PMID: 37441807 DOI: 10.1016/j.intimp.2023.110594] [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: 02/15/2023] [Revised: 06/13/2023] [Accepted: 06/30/2023] [Indexed: 07/15/2023]
Abstract
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with few pharmacological treatments. Minocycline, a tetracycline derivative that inhibits microglial activation, has been well-identified with anti-inflammatory properties and neuroprotective effects. A growing body of research suggests that ASD is associated with neuroinflammation, abnormal neurotransmitter levels, and neurogenesis. Thus, we hypothesized that minocycline could improve autism-related behaviors by inhibiting microglia activation and altering neuroinflammation. To verify our hypothesis, we used a mouse model of autism, BTBR T + Itpr3tf/J (BTBR). As expected, minocycline administration rescued the sociability and repetitive, stereotyped behaviors of BTBR mice while having no effect in C57BL/6J mice. We also found that minocycline improved neurogenesis and inhibited microglia activation in the hippocampus of BTBR mice. In addition, minocycline treatment inhibited Erk1/2 phosphorylation in the hippocampus of BTBR mice. Our findings show that minocycline administration alleviates ASD-like behaviors in BTBR mice and improves neurogenesis, suggesting that minocycline supplementation might be a potential strategy for improving ASD symptoms.
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Affiliation(s)
- Yi Luo
- Department of Military Cognitive Psychology, School of Psychology, Army Medical University, Chongqing 400038, China
| | - Keyi Lv
- Department of Military Cognitive Psychology, School of Psychology, Army Medical University, Chongqing 400038, China
| | - Zhulin Du
- Department of Military Cognitive Psychology, School of Psychology, Army Medical University, Chongqing 400038, China; School of Life Sciences, Chongqing University, Chongqing 401331, China
| | - Dandan Zhang
- Department of Military Cognitive Psychology, School of Psychology, Army Medical University, Chongqing 400038, China
| | - Mei Chen
- Department of Military Cognitive Psychology, School of Psychology, Army Medical University, Chongqing 400038, China
| | - Jing Luo
- Department of Military Cognitive Psychology, School of Psychology, Army Medical University, Chongqing 400038, China
| | - Lian Wang
- Department of Military Cognitive Psychology, School of Psychology, Army Medical University, Chongqing 400038, China
| | - Tianyao Liu
- Department of Military Cognitive Psychology, School of Psychology, Army Medical University, Chongqing 400038, China
| | - Hong Gong
- Department of Military Cognitive Psychology, School of Psychology, Army Medical University, Chongqing 400038, China.
| | - Xiaotang Fan
- Department of Military Cognitive Psychology, School of Psychology, Army Medical University, Chongqing 400038, China.
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20
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Juckel G, Freund N. Microglia and microbiome in schizophrenia: can immunomodulation improve symptoms? J Neural Transm (Vienna) 2023; 130:1187-1193. [PMID: 36810627 PMCID: PMC10460707 DOI: 10.1007/s00702-023-02605-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 02/13/2023] [Indexed: 02/24/2023]
Abstract
In this overview, influences of microglia activation and disturbances of the microbiome in the devastating disorder schizophrenia are discussed. Despite previous assumptions of a primary neurodegenerative character of this disorder, current research underlines the important autoimmunological and inflammatory processes here. Early disturbances of microglial cells as well as cytokines could lead to weakness of the immunological system in the prodromal phase and then fully manifest in patients with schizophrenia. Measurements of microbiome features might allow identifying the prodromal phase. In conclusion, such thinking would imply several new therapeutic options regulating immune processes by old or new anti-inflammatory agents in patients.
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Affiliation(s)
- Georg Juckel
- Department of Psychiatry, Ruhr-University Bochum, LWL-University Hospital, Alexandrinenstr.1, 44791, Bochum, Germany.
| | - Nadja Freund
- Department of Psychiatry, Ruhr-University Bochum, LWL-University Hospital, Alexandrinenstr.1, 44791, Bochum, Germany
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21
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Guneykaya D, Ugursu B, Logiacco F, Popp O, Feiks MA, Meyer N, Wendt S, Semtner M, Cherif F, Gauthier C, Madore C, Yin Z, Çınar Ö, Arslan T, Gerevich Z, Mertins P, Butovsky O, Kettenmann H, Wolf SA. Sex-specific microglia state in the Neuroligin-4 knock-out mouse model of autism spectrum disorder. Brain Behav Immun 2023; 111:61-75. [PMID: 37001827 PMCID: PMC10330133 DOI: 10.1016/j.bbi.2023.03.023] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 03/15/2023] [Accepted: 03/27/2023] [Indexed: 04/10/2023] Open
Abstract
Neuroligin-4 (NLGN4) loss-of-function mutations are associated with monogenic heritable autism spectrum disorder (ASD) and cause alterations in both synaptic and behavioral phenotypes. Microglia, the resident CNS macrophages, are implicated in ASD development and progression. Here we studied the impact of NLGN4 loss in a mouse model, focusing on microglia phenotype and function in both male and female mice. NLGN4 depletion caused lower microglia density, less ramified morphology, reduced response to injury and purinergic signaling specifically in the hippocampal CA3 region predominantly in male mice. Proteomic analysis revealed disrupted energy metabolism in male microglia and provided further evidence for sexual dimorphism in the ASD associated microglial phenotype. In addition, we observed impaired gamma oscillations in a sex-dependent manner. Lastly, estradiol application in male NLGN4-/- mice restored the altered microglial phenotype and function. Together, these results indicate that loss of NLGN4 affects not only neuronal network activity, but also changes the microglia state in a sex-dependent manner that could be targeted by estradiol treatment.
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Affiliation(s)
- Dilansu Guneykaya
- Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Neurobiology, Harvard Medical School, Boston, USA
| | - Bilge Ugursu
- Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Germany; Psychoneuroimmunology, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Francesca Logiacco
- Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Oliver Popp
- Proteomics Platform, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin Institute of Health, Berlin, Germany
| | - Maria Almut Feiks
- Institute of Neurophysiology, Charité - Universitätsmedizin, Berlin, Germany
| | - Niklas Meyer
- Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Microbiology, Oslo University Hospital, Oslo, Norway
| | - Stefan Wendt
- Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Marcus Semtner
- Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Germany; Psychoneuroimmunology, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Fatma Cherif
- Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Christian Gauthier
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Charlotte Madore
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Univ. Bordeaux, INRA, Bordeaux INP, NutriNeuro, Bordeaux, France
| | - Zhuoran Yin
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Özcan Çınar
- Molecular Immunotherapy, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin Institute of Health, Berlin, Germany
| | - Taner Arslan
- Department of Oncology and Pathology, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden
| | - Zoltan Gerevich
- Institute of Neurophysiology, Charité - Universitätsmedizin, Berlin, Germany
| | - Philipp Mertins
- Proteomics Platform, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin Institute of Health, Berlin, Germany
| | - Oleg Butovsky
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Germany
| | - Helmut Kettenmann
- Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Susanne A Wolf
- Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Germany; Psychoneuroimmunology, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
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22
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Kotsiri I, Resta P, Spyrantis A, Panotopoulos C, Chaniotis D, Beloukas A, Magiorkinis E. Viral Infections and Schizophrenia: A Comprehensive Review. Viruses 2023; 15:1345. [PMID: 37376644 DOI: 10.3390/v15061345] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 06/02/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
Schizophrenia is a complex mental disorder with multiple genetic and environmental factors contributing to its pathogenesis. Viral infections have been suggested to be one of the environmental factors associated with the development of this disorder. We comprehensively review all relevant published literature focusing on the relationship between schizophrenia and various viral infections, such as influenza virus, herpes virus 1 and 2 (HSV-1 and HSV-2), cytomegalovirus (CMV), Epstein-Barr virus (EBV), retrovirus, coronavirus, and Borna virus. These viruses may interfere with the normal maturation of the brain directly or through immune-induced mediators, such as cytokines, leading to the onset of schizophrenia. Changes in the expression of critical genes and elevated levels of inflammatory cytokines have been linked to virally-induced infections and relevant immune activities in schizophrenia. Future research is necessary to understand this relationship better and provide insight into the molecular mechanisms underlying the pathophysiology of schizophrenia.
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Affiliation(s)
- Ioanna Kotsiri
- Department of Internal Medicine, Asklipeion General Hospital, Voulas, 16673 Athens, Greece
| | - Panagiota Resta
- Department of Biomedical Sciences, University of West Attica, 12243 Athens, Greece
- National AIDS Reference Centre of Southern Greece, Department of Public Health Policy, University of West Attica, 11521 Athens, Greece
| | - Alexandros Spyrantis
- Department of Internal Medicine, Asklipeion General Hospital, Voulas, 16673 Athens, Greece
| | | | - Dimitrios Chaniotis
- Department of Biomedical Sciences, University of West Attica, 12243 Athens, Greece
| | - Apostolos Beloukas
- Department of Biomedical Sciences, University of West Attica, 12243 Athens, Greece
- National AIDS Reference Centre of Southern Greece, Department of Public Health Policy, University of West Attica, 11521 Athens, Greece
| | - Emmanouil Magiorkinis
- Department of Laboratory Medicine, Sotiria General Hospital for Chest Diseases, 11527 Athens, Greece
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23
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Edemann-Callesen H, Bernhardt N, Hlusicka EB, Hintz F, Habelt B, Winter R, Neubert I, Pelz M, Filla A, Soto-Montenegro ML, Winter C, Hadar R. Supplement Treatment with NAC and Omega-3 Polyunsaturated Fatty Acids during Pregnancy Partially Prevents Schizophrenia-Related Outcomes in the Poly I:C Rat Model. Antioxidants (Basel) 2023; 12:antiox12051068. [PMID: 37237933 DOI: 10.3390/antiox12051068] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 05/02/2023] [Accepted: 05/04/2023] [Indexed: 05/28/2023] Open
Abstract
BACKGROUND Heightened levels of inflammation and oxidative stress are thought to be involved in the pathophysiology of schizophrenia. We aimed to assess whether intake of anti-inflammatory and anti-oxidant drugs during pregnancy prevents later schizophrenia-related outcomes in a neurodevelopmental rat model of this disorder. METHODS Pregnant Wistar rats were injected with polyriboinosinic-polyribocytidilic acid (Poly I:C) or saline and subsequently treated with either N-acetyl cysteine (NAC) or omega-3 polyunsaturated fatty acids (PUFAs) until delivery. Controls rats received no treatment. In the offspring, neuroinflammation and anti-oxidant enzyme activity were assessed on postnatal day (PND) 21, 33, 48, and 90. Behavioral testing was performed at PND 90, followed by post-mortem neurochemical assessment and ex vivo MRI. RESULTS The supplement treatment led to a quicker restoration of the wellbeing of dams. In the adolescent Poly I:C offspring, the supplement treatment prevented an increase in microglial activity and partially prevented a deregulation in the anti-oxidant defense system. In the adult Poly I:C offspring, supplement treatment partially prevented dopamine deficits, which was paralleled by some changes in behavior. Exposure to omega-3 PUFAs prevented the enlargement of lateral ventricles. CONCLUSION Intake of over-the-counter supplements may assist in especially targeting the inflammatory response related to schizophrenia pathophysiology, aiding in diminishing later disease severity in the offspring.
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Affiliation(s)
- Henriette Edemann-Callesen
- Department of Psychiatry and Neuroscience, Campus Mitte, Charité University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Nadine Bernhardt
- Department of Psychiatry and Psychotherapy, Medical Faculty Carl Gustav Carus, Technische Universität, 01307 Dresden, Germany
| | - Elizabeth Barroeta Hlusicka
- Department of Psychiatry and Psychotherapy, Medical Faculty Carl Gustav Carus, Technische Universität, 01307 Dresden, Germany
| | - Franziska Hintz
- Department of Psychiatry and Neuroscience, Campus Mitte, Charité University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Bettina Habelt
- Department of Psychiatry and Psychotherapy, Medical Faculty Carl Gustav Carus, Technische Universität, 01307 Dresden, Germany
- Leibniz Institute of Polymer Research Dresden, 01069 Dresden, Germany
| | - Rebecca Winter
- Department of Psychiatry and Psychotherapy, Medical Faculty Carl Gustav Carus, Technische Universität, 01307 Dresden, Germany
| | - Isabell Neubert
- Department of Psychiatry and Psychotherapy, Medical Faculty Carl Gustav Carus, Technische Universität, 01307 Dresden, Germany
| | - Meike Pelz
- Department of Psychiatry and Psychotherapy, Medical Faculty Carl Gustav Carus, Technische Universität, 01307 Dresden, Germany
| | - Alexandra Filla
- Department of Psychiatry and Psychotherapy, Medical Faculty Carl Gustav Carus, Technische Universität, 01307 Dresden, Germany
| | - Maria Luisa Soto-Montenegro
- Instituto de Investigación Sanitaria Gregorio Marañón, 28007 Madrid, Spain
- CIBER de Salud Mental, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Grupo de Investigación de Alto Rendimiento en Fisiopatología y Farmacología del Sistema Digestivo (NeuGut-URJC), Universidad Rey Juan Carlos, 28922 Alcorcón, Spain
| | - Christine Winter
- Department of Psychiatry and Neuroscience, Campus Mitte, Charité University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Ravit Hadar
- Department of Psychiatry and Neuroscience, Campus Mitte, Charité University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany
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24
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VanderZwaag J, Halvorson T, Dolhan K, Šimončičová E, Ben-Azu B, Tremblay MÈ. The Missing Piece? A Case for Microglia's Prominent Role in the Therapeutic Action of Anesthetics, Ketamine, and Psychedelics. Neurochem Res 2023; 48:1129-1166. [PMID: 36327017 DOI: 10.1007/s11064-022-03772-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 08/25/2022] [Accepted: 09/27/2022] [Indexed: 11/06/2022]
Abstract
There is much excitement surrounding recent research of promising, mechanistically novel psychotherapeutics - psychedelic, anesthetic, and dissociative agents - as they have demonstrated surprising efficacy in treating central nervous system (CNS) disorders, such as mood disorders and addiction. However, the mechanisms by which these drugs provide such profound psychological benefits are still to be fully elucidated. Microglia, the CNS's resident innate immune cells, are emerging as a cellular target for psychiatric disorders because of their critical role in regulating neuroplasticity and the inflammatory environment of the brain. The following paper is a review of recent literature surrounding these neuropharmacological therapies and their demonstrated or hypothesized interactions with microglia. Through investigating the mechanism of action of psychedelics, such as psilocybin and lysergic acid diethylamide, ketamine, and propofol, we demonstrate a largely under-investigated role for microglia in much of the emerging research surrounding these pharmacological agents. Among others, we detail sigma-1 receptors, serotonergic and γ-aminobutyric acid signalling, and tryptophan metabolism as pathways through which these agents modulate microglial phagocytic activity and inflammatory mediator release, inducing their therapeutic effects. The current review includes a discussion on future directions in the field of microglial pharmacology and covers bidirectional implications of microglia and these novel pharmacological agents in aging and age-related disease, glial cell heterogeneity, and state-of-the-art methodologies in microglial research.
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Affiliation(s)
- Jared VanderZwaag
- Neuroscience Graduate Program, University of Victoria, Victoria, BC, Canada
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Torin Halvorson
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
- BC Children's Hospital Research Institute, Vancouver, BC, Canada
| | - Kira Dolhan
- Department of Psychology, University of Victoria, Vancouver, BC, Canada
- Department of Biology, University of Victoria, Vancouver, BC, Canada
| | - Eva Šimončičová
- Neuroscience Graduate Program, University of Victoria, Victoria, BC, Canada
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Benneth Ben-Azu
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Department of Pharmacology, Faculty of Basic Medical Sciences, College of Health Sciences, Delta State University, Abraka, Delta State, Nigeria
| | - Marie-Ève Tremblay
- Neuroscience Graduate Program, University of Victoria, Victoria, BC, Canada.
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
- Département de médecine moléculaire, Université Laval, Québec City, QC, Canada.
- Axe Neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada.
- Neurology and Neurosurgery Department, McGill University, Montreal, QC, Canada.
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada.
- Institute for Aging and Lifelong Health, University of Victoria, Victoria, BC, Canada.
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25
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Logiacco F, Grzegorzek LC, Cordell EC, Popp O, Mertins P, Gutmann DH, Kettenmann H, Semtner M. Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic. Acta Neuropathol Commun 2023; 11:36. [PMID: 36890585 PMCID: PMC9996880 DOI: 10.1186/s40478-023-01525-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 02/05/2023] [Indexed: 03/10/2023] Open
Abstract
We previously discovered a sex-by-genotype defect in microglia function using a heterozygous germline knockout mouse model of Neurofibromatosis type 1 (Nf1 ± mice), in which only microglia from male Nf1 ± mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1 ± microglia exhibit differences in protein expression, which largely reflect pathways involved in cytoskeletal organization. In keeping with these predicted defects in cytoskeletal function, only male Nf1 ± microglia had reduced process arborization and surveillance capacity. To determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-CreER mice (Nf1flox/wt; Cx3cr1-CreER mice, Nf1MG ± mice). Surprisingly, neither male nor female Nf1MG ± mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP ± mice), the microglia defects found in Nf1 ± mice were recapitulated. Collectively, these data reveal that Nf1 ± sexually dimorphic microglia abnormalities are likely not cell-intrinsic properties, but rather reflect a response to Nf1 heterozygosity in other brain cells.
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Affiliation(s)
- Francesca Logiacco
- Cellular Neurosciences, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
- Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117, Berlin, Germany
| | - Laura Cathleen Grzegorzek
- Cellular Neurosciences, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
- Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117, Berlin, Germany
| | - Elizabeth C Cordell
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Oliver Popp
- Proteomics Platform, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
| | - Philipp Mertins
- Proteomics Platform, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
| | - David H Gutmann
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Helmut Kettenmann
- Cellular Neurosciences, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Marcus Semtner
- Cellular Neurosciences, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
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26
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Sleep Deprivation Induces Dopamine System Maladaptation and Escalated Corticotrophin-Releasing Factor Signaling in Adolescent Mice. Mol Neurobiol 2023; 60:3190-3209. [PMID: 36813955 DOI: 10.1007/s12035-023-03258-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 02/07/2023] [Indexed: 02/24/2023]
Abstract
Sleep disruption is highly associated with the pathogenesis and progression of a wild range of psychiatric disorders. Furthermore, appreciable evidence shows that experimental sleep deprivation (SD) on humans and rodents evokes anomalies in the dopaminergic (DA) signaling, which are also implicated in the development of psychiatric illnesses such as schizophrenia or substance abuse. Since adolescence is a vital period for the maturation of the DA system as well as the occurrence of mental disorders, the present studies aimed to investigate the impacts of SD on the DA system of adolescent mice. We found that 72 h SD elicited a hyperdopaminergic status, with increased sensitivity to the novel environment and amphetamine (Amph) challenge. Also, altered neuronal activity and expression of striatal DA receptors were noticed in the SD mice. Moreover, 72 h SD influenced the immune status in the striatum, with reduced microglial phagocytic capacity, primed microglial activation, and neuroinflammation. The abnormal neuronal and microglial activity were putatively provoked by the enhanced corticotrophin-releasing factor (CRF) signaling and sensitivity during the SD period. Together, our findings demonstrated the consequences of SD in adolescents including aberrant neuroendocrine, DA system, and inflammatory status. Sleep insufficiency is a risk factor for the aberration and neuropathology of psychiatric disorders.
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27
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Potter HG, Kowash HM, Woods RM, Revill G, Grime A, Deeney B, Burgess MA, Aarons T, Glazier JD, Neill JC, Hager R. Maternal behaviours and adult offspring behavioural deficits are predicted by maternal TNFα concentration in a rat model of neurodevelopmental disorders. Brain Behav Immun 2023; 108:162-175. [PMID: 36503051 DOI: 10.1016/j.bbi.2022.12.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/14/2022] [Accepted: 12/03/2022] [Indexed: 12/13/2022] Open
Abstract
Exposure to inflammatory stressors during fetal development is a major risk factor for neurodevelopmental disorders (NDDs) in adult offspring. Maternal immune activation (MIA), induced by infection, causes an acute increase in pro-inflammatory cytokines which can increase the risk for NDDs directly by inducing placental and fetal brain inflammation, or indirectly through affecting maternal care behaviours thereby affecting postnatal brain development. Which of these two potential mechanisms dominates in increasing offspring risk for NDDs remains unclear. Here, we show that acute systemic maternal inflammation induced by the viral mimetic polyinosinic:polycytidylic acid (poly I:C) on gestational day 15 of rat pregnancy affects offspring and maternal behaviour, offspring cognition, and expression of NDD-relevant genes in the offspring brain. Dams exposed to poly I:C elicited an acute increase in the pro-inflammatory cytokine tumour necrosis factor (TNF; referred to here as TNFα), which predicted disruption of key maternal care behaviours. Offspring of poly I:C-treated dams showed early behavioural and adult cognitive deficits correlated to the maternal TNFα response, but, importantly, not with altered maternal care. We also found interacting effects of sex and treatment on GABAergic gene expression and DNA methylation in these offspring in a brain region-specific manner, including increased parvalbumin expression in the female adolescent frontal cortex. We conclude that the MIA-induced elevation of TNFα in the maternal compartment affects fetal neurodevelopment leading to altered offspring behaviour and cognition. Our results suggest that a focus on prenatal pathways affecting fetal neurodevelopment would provide greater insights into the mechanisms underpinning the TNFα-mediated genesis of altered offspring behaviour and cognition following maternal inflammation.
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Affiliation(s)
- Harry G Potter
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom; School of Medicine, University of Central Lancashire, Burnley BB11 1RA, United Kingdom.
| | - Hager M Kowash
- Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, St Mary's Hospital, Manchester M13 9WL, United Kingdom
| | - Rebecca M Woods
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
| | - Grace Revill
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
| | - Amy Grime
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
| | - Brendan Deeney
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
| | - Matthew A Burgess
- Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
| | - Toby Aarons
- Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
| | - Jocelyn D Glazier
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
| | - Joanna C Neill
- Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom; Chair of Medical Psychedelics Working Group, Drug Science, United Kingdom
| | - Reinmar Hager
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
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28
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Breach MR, Lenz KM. Sex Differences in Neurodevelopmental Disorders: A Key Role for the Immune System. Curr Top Behav Neurosci 2023; 62:165-206. [PMID: 35435643 PMCID: PMC10286778 DOI: 10.1007/7854_2022_308] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Sex differences are prominent defining features of neurodevelopmental disorders. Understanding the sex biases in these disorders can shed light on mechanisms leading to relative risk and resilience for the disorders, as well as more broadly advance our understanding of how sex differences may relate to brain development. The prevalence of neurodevelopmental disorders is increasing, and the two most common neurodevelopmental disorders, Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) exhibit male-biases in prevalence rates and sex differences in symptomology. While the causes of neurodevelopmental disorders and their sex differences remain to be fully understood, increasing evidence suggests that the immune system plays a critical role in shaping development. In this chapter we discuss sex differences in prevalence and symptomology of ASD and ADHD, review sexual differentiation and immune regulation of neurodevelopment, and discuss findings from human and rodent studies of immune dysregulation and perinatal immune perturbation as they relate to potential mechanisms underlying neurodevelopmental disorders. This chapter will give an overview of how understanding sex differences in neuroimmune function in the context of neurodevelopmental disorders could lend insight into their etiologies and better treatment strategies.
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Affiliation(s)
- Michaela R Breach
- Neuroscience Graduate Program, The Ohio State University, Columbus, OH, USA
| | - Kathryn M Lenz
- Department of Psychology, The Ohio State University, Columbus, OH, USA.
- Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
- Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, USA.
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Amanollahi M, Jameie M, Rezaei N. Neuroinflammation as a potential therapeutic target in neuroimmunological diseases. TRANSLATIONAL NEUROIMMUNOLOGY, VOLUME 7 2023:475-504. [DOI: 10.1016/b978-0-323-85841-0.00021-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Jeon SW, Kim YK. Neuron-Microglia Crosstalk in Neuropsychiatric Disorders. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1411:3-15. [PMID: 36949303 DOI: 10.1007/978-981-19-7376-5_1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
Numerous studies have investigated the causes and mechanisms of psychiatric disorders through postmortem examination of patients with a history of a schizophrenia, mood disorder, or neurocognitive disorder. In addition, the search for specific mechanism-based treatments for psychiatric disorders has been intensified through the use of transgenic animal models involving specific genes tightly associated with psychiatric disorders. As a result, many studies with patients or animal models have reported a close association of neuroglia with major psychiatric disorders. Recently, research has focused on the associations between microglia and major psychiatric disorders and on the role of the immune response and abnormal microglia in the onset and symptoms of psychiatric disorders, in particular. Postmortem studies of brain tissue and animal models recapitulating human mental disorders have also confirmed association between psychiatric disorders and quantitative, structural, or functional abnormalities of neuron-microglia crosstalk. This review aims to describe the relationships between microglia and major psychiatric disorders and to specifically examine studies of gene expression and function of microglia in depression, schizophrenia, and Alzheimer's disease.
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Affiliation(s)
- Sang Won Jeon
- Department of Psychiatry, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Saemunan-ro, Jongno-gu, Republic of Korea
| | - Yong-Ku Kim
- Department of Psychiatry, College of Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea.
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Channer B, Matt SM, Nickoloff-Bybel EA, Pappa V, Agarwal Y, Wickman J, Gaskill PJ. Dopamine, Immunity, and Disease. Pharmacol Rev 2023; 75:62-158. [PMID: 36757901 PMCID: PMC9832385 DOI: 10.1124/pharmrev.122.000618] [Citation(s) in RCA: 104] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 12/14/2022] Open
Abstract
The neurotransmitter dopamine is a key factor in central nervous system (CNS) function, regulating many processes including reward, movement, and cognition. Dopamine also regulates critical functions in peripheral organs, such as blood pressure, renal activity, and intestinal motility. Beyond these functions, a growing body of evidence indicates that dopamine is an important immunoregulatory factor. Most types of immune cells express dopamine receptors and other dopaminergic proteins, and many immune cells take up, produce, store, and/or release dopamine, suggesting that dopaminergic immunomodulation is important for immune function. Targeting these pathways could be a promising avenue for the treatment of inflammation and disease, but despite increasing research in this area, data on the specific effects of dopamine on many immune cells and disease processes remain inconsistent and poorly understood. Therefore, this review integrates the current knowledge of the role of dopamine in immune cell function and inflammatory signaling across systems. We also discuss the current understanding of dopaminergic regulation of immune signaling in the CNS and peripheral tissues, highlighting the role of dopaminergic immunomodulation in diseases such as Parkinson's disease, several neuropsychiatric conditions, neurologic human immunodeficiency virus, inflammatory bowel disease, rheumatoid arthritis, and others. Careful consideration is given to the influence of experimental design on results, and we note a number of areas in need of further research. Overall, this review integrates our knowledge of dopaminergic immunology at the cellular, tissue, and disease level and prompts the development of therapeutics and strategies targeted toward ameliorating disease through dopaminergic regulation of immunity. SIGNIFICANCE STATEMENT: Canonically, dopamine is recognized as a neurotransmitter involved in the regulation of movement, cognition, and reward. However, dopamine also acts as an immune modulator in the central nervous system and periphery. This review comprehensively assesses the current knowledge of dopaminergic immunomodulation and the role of dopamine in disease pathogenesis at the cellular and tissue level. This will provide broad access to this information across fields, identify areas in need of further investigation, and drive the development of dopaminergic therapeutic strategies.
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Affiliation(s)
- Breana Channer
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Stephanie M Matt
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Emily A Nickoloff-Bybel
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Vasiliki Pappa
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Yash Agarwal
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Jason Wickman
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Peter J Gaskill
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
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Lorusso JM, Woods RM, McEwan F, Glazier JD, Neill JC, Harte M, Hager R. Clustering of cognitive phenotypes identifies susceptible and resilient offspring in a rat model of maternal immune activation and early-life stress. Brain Behav Immun Health 2022; 25:100514. [PMID: 36177307 PMCID: PMC9513103 DOI: 10.1016/j.bbih.2022.100514] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 09/13/2022] [Indexed: 11/30/2022] Open
Abstract
Schizophrenia and other neurodevelopmental disorders often have very heterogeneous symptoms, especially regarding cognition: while some individuals may exhibit deficient cognition, others are relatively unaffected. Studies using developmental animal models often ignore phenotypic heterogeneity in favour of traditional treatment/control comparisons. This may result in resilient or unaffected individuals masking the effects of susceptible individuals if grouped together. Here, we used maternal immune activation and limited bedding and nesting, respectively, as a two-hit neurodevelopmental model for schizophrenia. Both factors reduced cognitive function in a novel object recognition (NOR) task. While we found treatment group effects on cognitive phenotypes, behavioural clustering identified three subpopulations exposed to either insult: those exhibiting ‘typical’ cognitive performance on the NOR, an intermediate phenotype, or a marked deficit. These clusters included offspring from each treatment group, although both intermediate and marked deficit clusters were composed primarily of offspring from treated groups. Clustering allowed stratification within treatment groups into ‘susceptible’ and ‘resilient’ individuals, while also identifying conserved phenotypes across treatment groups. Using unbiased cluster analyses in preclinical models can better characterize phenotypes and enables a better understanding of both face and construct validity of phenotypic heterogeneity. The use of unbiased clustering techniques may help identify potential markers associated with individual susceptibility and resilience in neurodevelopmental disorder models.
Maternal immune activation and early life stress affect recognition memory. New groups were identified using unbiased clustering based on task performance. These clusters reflected high-, low-, and intermediary recognition memory. Treatment offspring were distributed across all three unbiased clusters. These findings suggest some offspring will be resilient to developmental insults.
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Affiliation(s)
- Jarred M. Lorusso
- Division of Evolution, Infection, and Genomics, School of Biological Sciences, Manchester Academic Health Science Centre, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PL, United Kingdom
- Corresponding author.
| | - Rebecca M. Woods
- Division of Evolution, Infection, and Genomics, School of Biological Sciences, Manchester Academic Health Science Centre, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PL, United Kingdom
| | - Francesca McEwan
- Division of Evolution, Infection, and Genomics, School of Biological Sciences, Manchester Academic Health Science Centre, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PL, United Kingdom
| | - Jocelyn D. Glazier
- Division of Evolution, Infection, and Genomics, School of Biological Sciences, Manchester Academic Health Science Centre, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PL, United Kingdom
| | - Joanna C. Neill
- Division of Pharmacy & Optometry, School of Health Sciences, Manchester Academic Health Science Centre, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PL, United Kingdom
| | - Michael Harte
- Division of Pharmacy & Optometry, School of Health Sciences, Manchester Academic Health Science Centre, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PL, United Kingdom
| | - Reinmar Hager
- Division of Evolution, Infection, and Genomics, School of Biological Sciences, Manchester Academic Health Science Centre, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PL, United Kingdom
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Otero AM, Antonson AM. At the crux of maternal immune activation: Viruses, microglia, microbes, and IL-17A. Immunol Rev 2022; 311:205-223. [PMID: 35979731 PMCID: PMC9804202 DOI: 10.1111/imr.13125] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Inflammation during prenatal development can be detrimental to neurodevelopmental processes, increasing the risk of neuropsychiatric disorders. Prenatal exposure to maternal viral infection during pregnancy is a leading environmental risk factor for manifestation of these disorders. Preclinical animal models of maternal immune activation (MIA), established to investigate this link, have revealed common immune and microbial signaling pathways that link mother and fetus and set the tone for prenatal neurodevelopment. In particular, maternal intestinal T helper 17 cells, educated by endogenous microbes, appear to be key drivers of effector IL-17A signals capable of reaching the fetal brain and causing neuropathologies. Fetal microglial cells are particularly sensitive to maternally derived inflammatory and microbial signals, and they shift their functional phenotype in response to MIA. Resulting cortical malformations and miswired interneuron circuits cause aberrant offspring behaviors that recapitulate core symptoms of human neurodevelopmental disorders. Still, the popular use of "sterile" immunostimulants to initiate MIA has limited translation to the clinic, as these stimulants fail to capture biologically relevant innate and adaptive inflammatory sequelae induced by live pathogen infection. Thus, there is a need for more translatable MIA models, with a focus on relevant pathogens like seasonal influenza viruses.
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Affiliation(s)
- Ashley M. Otero
- Neuroscience ProgramUniversity of Illinois Urbana‐ChampaignUrbanaIllinoisUSA
| | - Adrienne M. Antonson
- Department of Animal SciencesUniversity of Illinois Urbana‐ChampaignUrbanaIllinoisUSA
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Guerrin CGJ, Shoji A, Doorduin J, de Vries EFJ. Immune Activation in Pregnant Rats Affects Brain Glucose Consumption, Anxiety-like Behaviour and Recognition Memory in their Male Offspring. Mol Imaging Biol 2022; 24:740-749. [PMID: 35380336 PMCID: PMC9581871 DOI: 10.1007/s11307-022-01723-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 02/22/2022] [Accepted: 03/21/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE Prenatal infection during pregnancy is a risk factor for schizophrenia, as well as for other developmental psychiatric disorders, such as autism and bipolar disorder. Schizophrenia patients were reported to have altered brain metabolism and neuroinflammation. However, the link between prenatal infection, altered brain inflammation and metabolism, and schizophrenia remains unclear. In this project, we aimed to evaluate whether there are changes in brain glucose consumption and microglia activation in the offspring of pregnant rats exposed to maternal immune activation (MIA), and if so, whether these changes occur before or after the initiation of schizophrenia-like behaviour. PROCEDURES Pregnant rats were treated with the viral mimic polyinosinic-polycytidylic acid (MIA group) or saline (control group) on gestational day 15. Static PET scans of the male offspring were acquired on postnatal day (PND) 21, 60, and 90, using [11C]-PK11195 and deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) as tracers to measure TSPO expression in activated microglia and brain glucose consumption, respectively. On PND60 and PND90, anxiety-like behaviour, recognition memory, and sensorimotor gating were measured using the open field test (OFT), novel object recognition test (NOR), and prepulse inhibition test (PPI). RESULTS [18F]-FDG PET demonstrated that MIA offspring displayed higher brain glucose consumption in the whole brain after weaning (p = 0.017), and in the frontal cortex during late adolescence (p = 0.001) and adulthood (p = 0.037) than control rats. [11C]-PK11195 PET did not reveal any changes in TSPO expression in MIA offspring. Prenatal infection induced age-related behavioural alterations. Adolescent MIA offspring displayed a more anxious state in the OFT than controls (p = 0.042). Adult MIA offspring showed recognition memory deficits in the NOR (p = 0.003). Our study did not show any PPI deficits. CONCLUSIONS Our results suggest that prenatal immune activation changed neurodevelopment, resulting in increased brain glucose consumption, but not in microglia activation. The increased brain glucose consumption in the frontal cortex of MIA offspring remained until adulthood and was associated with increased anxiety-like behaviour during adolescence and recognition memory deficits in adulthood.
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Affiliation(s)
- Cyprien G J Guerrin
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713, GZ, Groningen, the Netherlands
| | - Alexandre Shoji
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713, GZ, Groningen, the Netherlands
| | - Janine Doorduin
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713, GZ, Groningen, the Netherlands
| | - Erik F J de Vries
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713, GZ, Groningen, the Netherlands.
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Yamada J, Maeda S, Soya M, Nishida H, Iinuma KM, Jinno S. Alleviation of cognitive deficits via upregulation of chondroitin sulfate biosynthesis by lignan sesamin in a mouse model of neuroinflammation. J Nutr Biochem 2022; 108:109093. [PMID: 35724814 DOI: 10.1016/j.jnutbio.2022.109093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 05/09/2022] [Accepted: 05/20/2022] [Indexed: 12/29/2022]
Abstract
Lignans are plant-derived compounds that act as partial estrogen agonists. Chondroitin sulfate proteoglycans (CSPGs) represent one of the major components of the extracellular matrix (ECM). Here we aimed to understand the role of sesamin (SES), a major lignan compound, in the biosynthesis and degradation of CSPGs in the mouse hippocampus because CSPGs play a key role in the regulation of cognitive functions through the promotion of adult neurogenesis. The expression of the pro-inflammatory cytokine interleukin-1β was decreased by SES administration in the hippocampus of lipopolysaccharide (LPS)-treated mice, a model of neuroinflammation-induced cognitive deficits. The expression of genes related to biosynthesis and degradation of CSPGs in the hippocampus of LPS-treated mice was both increased and decreased by SES administration. Further, the diffuse ECM labeling of CSPGs by Wisteria floribunda agglutinin (WFA) in the hippocampus of LPS-treated mice was increased by SES administration. The densities of neural stem cells, late transit-amplifying cells, and newborn-granule cells in the hippocampus of LPS-treated mice were also increased by SES administration. Moreover, SES-induced alterations in gene expression, WFA labeling, and adult neurogenesis in LPS-treated mice were more evident in the dorsal hippocampus (center of cognition) than in the ventral hippocampus (center of emotion). Neither LPS nor SES administration affected locomotor activity, anxiety-like behavior, and depression-related behavior. However, impairments in contextual memory and sensorimotor gating in LPS-treated mice were recovered by SES administration. Our results show that SES can promote adult hippocampal neurogenesis through the upregulation of CSPGs, which may alleviate cognitive deficits induced by neuroinflammation.
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Affiliation(s)
- Jun Yamada
- Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shoichiro Maeda
- Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Mariko Soya
- Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hidefumi Nishida
- Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kyoko M Iinuma
- Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shozo Jinno
- Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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Structural and Functional Deviations of the Hippocampus in Schizophrenia and Schizophrenia Animal Models. Int J Mol Sci 2022; 23:ijms23105482. [PMID: 35628292 PMCID: PMC9143100 DOI: 10.3390/ijms23105482] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/09/2022] [Accepted: 05/11/2022] [Indexed: 01/04/2023] Open
Abstract
Schizophrenia is a grave neuropsychiatric disease which frequently onsets between the end of adolescence and the beginning of adulthood. It is characterized by a variety of neuropsychiatric abnormalities which are categorized into positive, negative and cognitive symptoms. Most therapeutical strategies address the positive symptoms by antagonizing D2-dopamine-receptors (DR). However, negative and cognitive symptoms persist and highly impair the life quality of patients due to their disabling effects. Interestingly, hippocampal deviations are a hallmark of schizophrenia and can be observed in early as well as advanced phases of the disease progression. These alterations are commonly accompanied by a rise in neuronal activity. Therefore, hippocampal formation plays an important role in the manifestation of schizophrenia. Furthermore, studies with animal models revealed a link between environmental risk factors and morphological as well as electrophysiological abnormalities in the hippocampus. Here, we review recent findings on structural and functional hippocampal abnormalities in schizophrenic patients and in schizophrenia animal models, and we give an overview on current experimental approaches that especially target the hippocampus. A better understanding of hippocampal aberrations in schizophrenia might clarify their impact on the manifestation and on the outcome of this severe disease.
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Effect of dimethyl fumarate on the changes in the medial prefrontal cortex structure and behavior in the poly(I:C)-induced maternal immune activation model of schizophrenia in the male mice. Behav Brain Res 2022; 417:113581. [PMID: 34530042 DOI: 10.1016/j.bbr.2021.113581] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/31/2021] [Accepted: 09/09/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND The link between maternal immune activation (MIA) and the risk of developing schizophrenia (SCZ) later in life has been of major focus in recent years. This link could be bridged by activated inflammatory pathways and excessive cytokine release resulting in adverse effects on behavior, histology, and cytoarchitecture. The down-regulatory effects of immunomodulatory agents on the activated glial cells and their therapeutic effects on schizophrenic patients are consistent with this hypothesis. OBJECTIVE We investigated whether treatment with the anti-inflammatory drug dimethyl fumarate (DMF) could rescue impacts of prenatal exposure to polyinosinic:polycytidylic acid [poly (I:C)]. METHODS Pregnant dams were administered poly(I:C) at gestational day 9.5. Offspring born from these mothers were treated with DMF for fourteen consecutive days from postnatal day 80 and were assessed behaviorally before and after treatment. The brains were then stained with Cresyl Violet or Golgi-Cox. In addition to the estimation of stereological parameters, cytoarchitectural changes were also evaluated in the medial prefrontal cortex. RESULTS MIA caused some abnormalities in behavior, as well as changes in the number of neurons and non-neurons. These alterations were also extended to pyramidal layer III neurons with a significant decrease in dendritic complexity and spine density which DMF treatment could prevent these changes. Furthermore, DMF treatment was also effective against abnormal exploratory and depression-related behavior, but not the changes in the number of cells. CONCLUSION These findings support the idea of using anti-inflammatory agents as adjunctive therapy in patients with SCZ.
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Carloni E, Ramos A, Hayes LN. Developmental Stressors Induce Innate Immune Memory in Microglia and Contribute to Disease Risk. Int J Mol Sci 2021; 22:13035. [PMID: 34884841 PMCID: PMC8657756 DOI: 10.3390/ijms222313035] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 12/26/2022] Open
Abstract
Many types of stressors have an impact on brain development, function, and disease susceptibility including immune stressors, psychosocial stressors, and exposure to drugs of abuse. We propose that these diverse developmental stressors may utilize a common mechanism that underlies impaired cognitive function and neurodevelopmental disorders such as schizophrenia, autism, and mood disorders that can develop in later life as a result of developmental stressors. While these stressors are directed at critical developmental windows, their impacts are long-lasting. Immune activation is a shared pathophysiology across several different developmental stressors and may thus be a targetable treatment to mitigate the later behavioral deficits. In this review, we explore different types of prenatal and perinatal stressors and their contribution to disease risk and underlying molecular mechanisms. We highlight the impact of developmental stressors on microglia biology because of their early infiltration into the brain, their critical role in brain development and function, and their long-lived status in the brain throughout life. Furthermore, we introduce innate immune memory as a potential underlying mechanism for developmental stressors' impact on disease. Finally, we highlight the molecular and epigenetic reprogramming that is known to underlie innate immune memory and explain how similar molecular mechanisms may be at work for cells to retain a long-term perturbation after exposure to developmental stressors.
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Affiliation(s)
- Elisa Carloni
- Department of Molecular and Cellular Biology, Dartmouth College, Hanover, NH 03755, USA;
| | - Adriana Ramos
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA;
| | - Lindsay N. Hayes
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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Carrier M, Šimončičová E, St-Pierre MK, McKee C, Tremblay MÈ. Psychological Stress as a Risk Factor for Accelerated Cellular Aging and Cognitive Decline: The Involvement of Microglia-Neuron Crosstalk. Front Mol Neurosci 2021; 14:749737. [PMID: 34803607 PMCID: PMC8599581 DOI: 10.3389/fnmol.2021.749737] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/16/2021] [Indexed: 12/22/2022] Open
Abstract
The relationship between the central nervous system (CNS) and microglia is lifelong. Microglia originate in the embryonic yolk sac during development and populate the CNS before the blood-brain barrier forms. In the CNS, they constitute a self-renewing population. Although they represent up to 10% of all brain cells, we are only beginning to understand how much brain homeostasis relies on their physiological functions. Often compared to a double-edged sword, microglia hold the potential to exert neuroprotective roles that can also exacerbate neurodegeneration once compromised. Microglia can promote synaptic growth in addition to eliminating synapses that are less active. Synaptic loss, which is considered one of the best pathological correlates of cognitive decline, is a distinctive feature of major depressive disorder (MDD) and cognitive aging. Long-term psychological stress accelerates cellular aging and predisposes to various diseases, including MDD, and cognitive decline. Among the underlying mechanisms, stress-induced neuroinflammation alters microglial interactions with the surrounding parenchymal cells and exacerbates oxidative burden and cellular damage, hence inducing changes in microglia and neurons typical of cognitive aging. Focusing on microglial interactions with neurons and their synapses, this review discusses the disrupted communication between these cells, notably involving fractalkine signaling and the triggering receptor expressed on myeloid cells (TREM). Overall, chronic stress emerges as a key player in cellular aging by altering the microglial sensome, notably via fractalkine signaling deficiency. To study cellular aging, novel positron emission tomography radiotracers for TREM and the purinergic family of receptors show interest for human study.
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Affiliation(s)
- Micaël Carrier
- Axe Neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada.,Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Eva Šimončičová
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Marie-Kim St-Pierre
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.,Department of Molecular Medicine, Université Laval, Québec City, QC, Canada
| | - Chloe McKee
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.,Department of Biology, University of Victoria, Victoria, BC, Canada
| | - Marie-Ève Tremblay
- Axe Neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada.,Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.,Department of Molecular Medicine, Université Laval, Québec City, QC, Canada.,Neurology and Neurosurgery Department, McGill University, Montreal, QC, Canada.,Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada
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40
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Mousaviyan R, Davoodian N, Alizadeh F, Ghasemi-Kasman M, Mousavi SA, Shaerzadeh F, Kazemi H. Zinc Supplementation During Pregnancy Alleviates Lipopolysaccharide-Induced Glial Activation and Inflammatory Markers Expression in a Rat Model of Maternal Immune Activation. Biol Trace Elem Res 2021; 199:4193-4204. [PMID: 33400154 DOI: 10.1007/s12011-020-02553-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 12/17/2020] [Indexed: 12/22/2022]
Abstract
Maternal immune activation (MIA) model has been profoundly described as a suitable approach to study the pathophysiological mechanisms of neuropsychiatric disorders, including schizophrenia. Our previous study revealed that prenatal exposure to lipopolysaccharide (LPS) induced working memory impairments in only male offspring. Based on the putative role of prefrontal cortex (PFC) in working memory process, the current study was conducted to examine the long-lasting effect of LPS-induced MIA on several neuroinflammatory mediators in the PFC of adult male pups. We also investigated whether maternal zinc supplementation can alleviate LPS-induced alterations in this region. Pregnant rats received intraperitoneal injections of either LPS (0.5 mg/kg) or saline on gestation days 15/16 and supplemented with ZnSO4 (30 mg/kg) throughout pregnancy. At postnatal day 60, the density of both microglia and astrocyte cells and the expression levels of IL-6, IL-1β, iNOS, TNF-α, NF-κB, and GFAP were evaluated in the PFC of male pups. Although maternal LPS treatment increased microglia and astrocyte density, number of neurons in the PFC of adult offspring remained unchanged. These findings were accompanied by the exacerbated mRNA levels of IL-6, IL-1β, iNOS, TNF-α, NF-κB, and GFAP as well. Conversely, prenatal zinc supplementation alleviated the mentioned alterations induced by LPS. These findings support the idea that the deleterious effects of prenatal LPS exposure could be attenuated by zinc supplementation during pregnancy. It is of interest to suggest early therapeutic intervention as a valuable approach to prevent neurodevelopmental deficits, following maternal infection. Schematic diagram describing the experimental timeline. On gestation days (GD) 15 and 16, pregnant dams were administered with intraperitoneal injections of either LPS (0.5 mg/kg) or vehicle and supplemented with ZnSO4 (30 mg/kg) throughout pregnancy by gavage. The resulting offspring were submitted to qPCR, immunostaining, and morphological analysis at PND 60. Maternal zinc supplementation alleviated increased expression levels of inflammatory mediators and microglia and astrocyte density induced by LPS in the PFC of treated offspring. PND postnatal day, PFC prefrontal cortex.
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Affiliation(s)
- Ronak Mousaviyan
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Nahid Davoodian
- Endocrinology and Metabolism Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
- Department of Clinical Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
| | - Faezeh Alizadeh
- Department of Clinical Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Maryam Ghasemi-Kasman
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
- Neuroscience Reesearch Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Seyed Abdollah Mousavi
- Pathology Department, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Fatemeh Shaerzadeh
- Department of Neuroscience, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, FL, 32610, USA
| | - Haniyeh Kazemi
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
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41
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Chauhan P, Kaur G, Prasad R, Singh H. Pharmacotherapy of schizophrenia: immunological aspects and potential role of immunotherapy. Expert Rev Neurother 2021; 21:1441-1453. [PMID: 34654348 DOI: 10.1080/14737175.2021.1994857] [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] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Schizophrenia is a complex disorder owing to diversity in clinical phenotypes, overlapping symptoms, and heterogeneous clinical presentation. Even after decades of research, the exact causative mechanisms of schizophrenia are not completely known. Recent evidence indicates the role of immune dysfunction in schizophrenia pathogenesis as observed from alteration in immune cells, increased activity of complement cascade, and development of autoantibodies against neurotransmitter receptors. Immunotherapy involving immunosuppressants and cytokine-targeting drugs, have shown promising results in several clinical studies and it demands further research in this area. AREAS COVERED Here, the authors review the immunopathogenesis of schizophrenia, limitations of conventional, and atypical antipsychotic drugs and the potential role and limitations of immunotherapeutic drugs in schizophrenia management. EXPERT OPINION Schizophrenia is a complex disorder and poses a challenge to the currently available treatment approaches. Nearly 30% schizophrenia patients exhibit minimal response toward conventional and atypical antipsychotic drugs. Immune system dysfunction plays an important part of schizophrenia pathophysiology and existing monoclonal antibody (mAb) drugs targeting specific components of the immune system are being repositioned in schizophrenia. The authors call upon public and private funders to facilitate urgent and rigorous research efforts in exploring potential role of immunotherapy in schizophrenia.
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Affiliation(s)
- Prerna Chauhan
- Multidisciplinary Research Unit, Government Medical College & Hospital, Chandigarh, India
| | - Gurjit Kaur
- Department of Physiology, Government Medical College & Hospital, Chandigarh, India
| | - Rajendra Prasad
- Department of Biochemistry, Maharishi Markandeshwar Institute of Medical Sciences and Research, Ambala, Haryana, India
| | - Harmanjit Singh
- Department of Pharmacology, Government Medical College & Hospital, Chandigarh, India
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42
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Scheuer T, dem Brinke EA, Grosser S, Wolf SA, Mattei D, Sharkovska Y, Barthel PC, Endesfelder S, Friedrich V, Bührer C, Vida I, Schmitz T. Reduction of cortical parvalbumin-expressing GABAergic interneurons in a rodent hyperoxia model of preterm birth brain injury with deficits in social behavior and cognition. Development 2021; 148:272278. [PMID: 34557899 DOI: 10.1242/dev.198390] [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: 11/11/2020] [Accepted: 09/17/2021] [Indexed: 12/18/2022]
Abstract
The inhibitory GABAergic system in the brain is involved in the etiology of various psychiatric problems, including autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD) and others. These disorders are influenced not only by genetic but also by environmental factors, such as preterm birth, although the underlying mechanisms are not known. In a translational hyperoxia model, exposing mice pups at P5 to 80% oxygen for 48 h to mimic a steep rise of oxygen exposure caused by preterm birth from in utero into room air, we documented a persistent reduction of cortical mature parvalbumin-expressing interneurons until adulthood. Developmental delay of cortical myelin was observed, together with decreased expression of oligodendroglial glial cell-derived neurotrophic factor (GDNF), a factor involved in interneuronal development. Electrophysiological and morphological properties of remaining interneurons were unaffected. Behavioral deficits were observed for social interaction, learning and attention. These results demonstrate that neonatal oxidative stress can lead to decreased interneuron density and to psychiatric symptoms. The obtained cortical myelin deficit and decreased oligodendroglial GDNF expression indicate that an impaired oligodendroglial-interneuronal interplay contributes to interneuronal damage.
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Affiliation(s)
- Till Scheuer
- Department of Neonatology, Charité - Universitätsmedizin Berlin, Berlin 13353, Germany
| | - Elena Auf dem Brinke
- Department of Neonatology, Charité - Universitätsmedizin Berlin, Berlin 13353, Germany
| | - Sabine Grosser
- Institute for Integrative Neuroanatomy, NeuroCure Cluster of Excellence, Charité - Universitätsmedizin Berlin, Berlin 10117, Germany
| | - Susanne A Wolf
- Cellular Neurocience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin 13125, Germany.,Department of Experimental Ophthalmology, Charité - Universitätsmedizin Berlin, Berlin 13353, Germany
| | - Daniele Mattei
- Cellular Neurocience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin 13125, Germany.,Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich CH-8057, Switzerland
| | - Yuliya Sharkovska
- Department of Neonatology, Charité - Universitätsmedizin Berlin, Berlin 13353, Germany.,Institute for Cell and Neurobiology, Center for Anatomy, Charité - Universitätsmedizin Berlin, Berlin 10117, Germany.,Berlin Institute of Health (BIH), Berlin 10178, Germany
| | - Paula C Barthel
- Department of Neonatology, Charité - Universitätsmedizin Berlin, Berlin 13353, Germany.,Institute for Cell and Neurobiology, Center for Anatomy, Charité - Universitätsmedizin Berlin, Berlin 10117, Germany
| | - Stefanie Endesfelder
- Department of Neonatology, Charité - Universitätsmedizin Berlin, Berlin 13353, Germany
| | - Vivien Friedrich
- Department of Neonatology, Charité - Universitätsmedizin Berlin, Berlin 13353, Germany.,Berlin Institute of Health (BIH), Berlin 10178, Germany
| | - Christoph Bührer
- Department of Neonatology, Charité - Universitätsmedizin Berlin, Berlin 13353, Germany
| | - Imre Vida
- Institute for Integrative Neuroanatomy, NeuroCure Cluster of Excellence, Charité - Universitätsmedizin Berlin, Berlin 10117, Germany
| | - Thomas Schmitz
- Department of Neonatology, Charité - Universitätsmedizin Berlin, Berlin 13353, Germany
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43
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Couch ACM, Berger T, Hanger B, Matuleviciute R, Srivastava DP, Thuret S, Vernon AC. Maternal immune activation primes deficiencies in adult hippocampal neurogenesis. Brain Behav Immun 2021; 97:410-422. [PMID: 34352366 PMCID: PMC8478664 DOI: 10.1016/j.bbi.2021.07.021] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 06/25/2021] [Accepted: 07/28/2021] [Indexed: 12/19/2022] Open
Abstract
Neurogenesis, the process in which new neurons are generated, occurs throughout life in the mammalian hippocampus. Decreased adult hippocampal neurogenesis (AHN) is a common feature across psychiatric disorders, including schizophrenia, depression- and anxiety-related behaviours, and is highly regulated by environmental influences. Epidemiological studies have consistently implicated maternal immune activation (MIA) during neurodevelopment as a risk factor for psychiatric disorders in adulthood. The extent to which the reduction of hippocampal neurogenesis in adulthood may be driven by early life exposures, such as MIA, is however unclear. We therefore reviewed the literature for evidence of the involvement of MIA in disrupting AHN. Consistent with our hypothesis, data from both in vivo murine and in vitro human models of AHN provide evidence for key roles of specific cytokines induced by MIA in the foetal brain in disrupting hippocampal neural progenitor cell proliferation and differentiation early in development. The precise molecular mechanisms however remain unclear. Nonetheless, these data suggest a potential latent vulnerability mechanism, whereby MIA primes dysfunction in the unique hippocampal pool of neural stem/progenitor cells. This renders offspring potentially more susceptible to additional environmental exposures later in life, such as chronic stress, resulting in the unmasking of psychopathology. We highlight the need for studies to test this hypothesis using validated animal models of MIA, but also to test the relevance of such data for human pathology at a molecular basis through the use of patient-derived induced pluripotent stem cells (hiPSC) differentiated into hippocampal progenitor cells.
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Affiliation(s)
- Amalie C M Couch
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK
| | - Thomas Berger
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Bjørn Hanger
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK
| | | | - Deepak P Srivastava
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK
| | - Sandrine Thuret
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Anthony C Vernon
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK.
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44
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Fernández de Cossío L, Lacabanne C, Bordeleau M, Castino G, Kyriakakis P, Tremblay MÈ. Lipopolysaccharide-induced maternal immune activation modulates microglial CX3CR1 protein expression and morphological phenotype in the hippocampus and dentate gyrus, resulting in cognitive inflexibility during late adolescence. Brain Behav Immun 2021; 97:440-454. [PMID: 34343619 DOI: 10.1016/j.bbi.2021.07.025] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 07/25/2021] [Accepted: 07/28/2021] [Indexed: 12/26/2022] Open
Abstract
Inflammation during pregnancy can disturb brain development and lead to disorders in the progeny, including autism spectrum disorder and schizophrenia. However, the mechanism by which a prenatal, short-lived increase of cytokines results in adverse neurodevelopmental outcomes remains largely unknown. Microglia-the brain's resident immune-cells-stand as fundamental cellular mediators, being highly sensitive and responsive to immune signals, which also play key roles during normal development. The fractalkine signaling axis is a neuron-microglia communication mechanism used to regulate neurogenesis and network formation. Previously, we showed hippocampal reduction of fractalkine receptor (Cx3cr1) mRNA at postnatal day (P) 15 in male offspring exposed to maternal immune activation induced with lipopolysaccharide (LPS) during late gestation, which was concomitant to an increased dendritic spine density in the dentate gyrus, a neurogenic niche. The current study sought to evaluate the origin and impact of this reduced hippocampal Cx3cr1 mRNA expression on microglia and cognition. We found that microglial total cell number and density are not affected in the dorsal hippocampus and dentate gyrus, respectively, but that the microglial CX3CR1 protein is decreased in the hippocampus of LPS-male offspring at P15. Further characterization of microglial morphology in the dentate gyrus identified a more ameboid phenotype in LPS-exposed offspring, predominantly in males, at P15. We thus explored maternal plasma and fetal brain cytokines to understand the mechanism behind microglial priming, showing a robust immune activation in the mother at 2 and 4 hrs after LPS administration, while only IL-10 tended towards upregulation at 2 hrs after LPS in fetal brains. To evaluate the functional long-term consequences, we assessed learning and cognitive flexibility behavior during late adolescence, finding that LPS affects only the latter with a male predominance on perseveration. A CX3CR1 gene variant in humans that results in disrupted fractalkine signaling has been recently associated with an increased risk for neurodevelopmental disorders. We show that an acute immune insult during late gestation can alter fractalkine signaling by reducing the microglial CX3CR1 protein expression, highlighting neuron-microglial fractalkine signaling as a relevant target underlying the outcomes of environmental risk factors on neurodevelopmental disorders.
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Affiliation(s)
- Lourdes Fernández de Cossío
- Department of Neurosciences, University of California, La Jolla, CA, USA; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
| | - Chloé Lacabanne
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
| | - Maude Bordeleau
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada; Axe Neurosciences, Centre de Recherche du CHU de Québec - Université Laval, Québec, QC, Canada
| | - Garance Castino
- Department of Biology, École Normale Supérieure de Lyon, Université de Lyon, Lyon, France
| | | | - Marie-Ève Tremblay
- Axe Neurosciences, Centre de Recherche du CHU de Québec - Université Laval, Québec, QC, Canada; Département de médecine moléculaire, Université Laval, Québec, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada; Division of Medical Sciences, University of Victoria, Victoria, BC, Canada; Biochemistry and Molecular Biology, Faculty of Medicine, The University of British Colombia, Vancouver, BC, Canada.
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Hameete BC, Fernández-Calleja JM, de Groot MW, Oppewal TR, Tiemessen MM, Hogenkamp A, de Vries RB, Groenink L. The poly(I:C)-induced maternal immune activation model; a systematic review and meta-analysis of cytokine levels in the offspring. Brain Behav Immun Health 2021; 11:100192. [PMID: 34589729 PMCID: PMC8474626 DOI: 10.1016/j.bbih.2020.100192] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 12/19/2022] Open
Abstract
The maternal polyinosinic:polycytidylic acid (poly(I:C)) animal model is frequently used to study how maternal immune activation may impact neuro development in the offspring. Here, we present the first systematic review and meta-analysis on the effects of maternal poly(I:C) injection on immune mediators in the offspring and provide an openly accessible systematic map of the data including methodological characteristics. Pubmed and EMBASE were searched for relevant publications, yielding 45 unique papers that met inclusion criteria. We extracted data on immune outcomes and methodological characteristics, and assessed the risk of bias. The descriptive summary showed that most studies reported an absence of effect, with an equal number of studies reporting an increase or decrease in the immune mediator being studied. Meta-analysis showed increased IL-6 concentrations in the offspring of poly(I:C) exposed mothers. This effect appeared larger prenatally than post-weaning. Furthermore, poly(I:C) administration during mid-gestation was associated with higher IL-6 concentrations in the offspring. Maternal poly(I:C) induced changes in IL-1β, Il-10 and TNF-α concentrations were small and could not be associated with age of offspring, gestational period or sampling location. Finally, quality of reporting of potential measures to minimize bias was low, which stresses the importance of adherence to publication guidelines. Since neurodevelopmental disorders in humans tend to be associated with lifelong changes in cytokine concentrations, the absence of these effects as identified in this systematic review may suggest that combining the model with other etiological factors in future studies may provide further insight in the mechanisms through which maternal immune activation affects neurodevelopment.
Long-term effects of maternal poly(I:C) on immune mediators in the offspring appear limited. Prenatal measurements and mid gestation poly(I:C) injection are associated with increases in IL-6 concentrations. Variety in methodological conduct hampers identification of key elements that affect cytokine concentrations. The quality of reporting of potential measures to minimize bias is poor.
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Affiliation(s)
- Bart C. Hameete
- Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, Utrecht, 3584 CG, the Netherlands
| | - José M.S. Fernández-Calleja
- Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, Utrecht, 3584 CG, the Netherlands
| | - Martje W.G.D.M. de Groot
- Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, Utrecht, 3584 CG, the Netherlands
| | - Titia Rixt Oppewal
- University College Utrecht (UCU), Campusplein 1, Utrecht, 3584 ED, the Netherlands
- Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, Groningen, 9747 AG, the Netherlands
| | - Machteld M. Tiemessen
- Research & Innovation, GCoE Immunology, Danone Nutricia Research, Uppsalalaan 12, Utrecht, 3584 CT, the Netherlands
| | - Astrid Hogenkamp
- Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, Utrecht, 3584 CG, the Netherlands
| | - Rob B.M. de Vries
- SYstematic Review Center for Laboratory (Animal) Experimentation, Department for Health Evidence, Radboud University Medical Center, Geert Grooteplein zuid 10, Nijmegen, 6525 GA, the Netherlands
| | - Lucianne Groenink
- Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, Utrecht, 3584 CG, the Netherlands
- Corresponding author.
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46
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Tremblay MÈ. Microglial functional alteration and increased diversity in the challenged brain: Insights into novel targets for intervention. Brain Behav Immun Health 2021; 16:100301. [PMID: 34589793 PMCID: PMC8474548 DOI: 10.1016/j.bbih.2021.100301] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 07/12/2021] [Accepted: 07/13/2021] [Indexed: 02/07/2023] Open
Abstract
Microglia are the resident immune cells of the central nervous system (CNS) parenchyma, which perform beneficial physiological roles across life. These immune cells actively maintain CNS health by clearing toxic debris and removing dysfunctional or degenerating cells. They also modify the wiring of neuronal circuits, by acting on the formation, modification, and elimination of synapses-the connections between neurons. Microglia furthermore recently emerged as highly diverse cells comprising several structural and functional states, indicating a far more critical involvement in orchestrating brain development, plasticity, behaviour, and cognition. Various environmental factors, together with the individual genetic predispositions, confer an increased risk for neurodevelopmental and neuropsychiatric disorders, as well as neurodegenerative diseases that include autism spectrum disorders, schizophrenia, major depressive disorder, and Alzheimer's disease, across life. Microglia are highly sensitive to chronic psychological stress, inadequate diet, viral/bacterial infection, pollution, and insufficient or altered sleep, especially during critical developmental periods, but also throughout life. These environmental challenges can compromise microglial physiological functions, resulting notably in defective neuronal circuit wiring, altered brain functional connectivity, and the onset of behavioral deficits into adolescence, adulthood, and aging. This short review provides a historical and technical perspective, notably focused on my contribution to the field, on how environmental challenges affect microglia, particularly their physiological functions, and increase their diversity, which provides novel targets for intervention.
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Affiliation(s)
- Marie-Ève Tremblay
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Québec, QC, Canada
- Molecular Medicine Department, Université Laval, Québec City, QC, Canada
- Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- The Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada
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47
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Meighan W, Elston TW, Bilkey D, Ward RD. Impaired discrimination of a subanesthetic dose of ketamine in a maternal immune activation model of schizophrenia risk. J Psychopharmacol 2021; 35:1141-1151. [PMID: 34229522 DOI: 10.1177/02698811211029739] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Animal models of psychiatric diseases suffer from a lack of reliable methods for accurate assessment of subjective internal states in nonhumans. This gap makes translation of results from animal models to patients particularly challenging. AIMS/METHODS Here, we used the drug-discrimination paradigm to allow rats that model a risk factor for schizophrenia (maternal immune activation, MIA) to report on the subjective internal state produced by a subanesthetic dose of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. RESULTS/OUTCOMES The MIA rats' discrimination of ketamine was impaired relative to controls, both in the total number of rats that acquired and the asymptotic level of discrimination accuracy. This deficit was not due to a general inability to learn to discriminate an internal drug cue or internal state generally, as MIA rats were unimpaired in the learning and acquisition of a morphine drug discrimination and were as sensitive to the internal state of satiety as controls. Furthermore, the deficit was not due to a decreased sensitivity to the physiological effects of ketamine, as MIA rats showed increased ketamine-induced locomotor activity. Finally, impaired discrimination of ketamine was only seen at subanesthetic doses which functionally correspond to psychotomimetic doses in humans. CONCLUSION These data link changes in NMDA responses to the MIA model. Furthermore, they confirm the utility of the drug-discrimination paradigm for future inquiries into the subjective internal state produced in models of schizophrenia and other developmental diseases.
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Affiliation(s)
- Wayne Meighan
- Department of Psychology, University of Otago, Dunedin, Otago, New Zealand
| | - Thomas W Elston
- Institute for Neurobiology, University of Tübingen, Tubingen, Baden-Württemberg, Germany.,Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA
| | - David Bilkey
- Department of Psychology, University of Otago, Dunedin, Otago, New Zealand
| | - Ryan D Ward
- Department of Psychology, University of Otago, Dunedin, Otago, New Zealand
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48
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Woods RM, Lorusso JM, Potter HG, Neill JC, Glazier JD, Hager R. Maternal immune activation in rodent models: A systematic review of neurodevelopmental changes in gene expression and epigenetic modulation in the offspring brain. Neurosci Biobehav Rev 2021; 129:389-421. [PMID: 34280428 DOI: 10.1016/j.neubiorev.2021.07.015] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 05/11/2021] [Accepted: 07/11/2021] [Indexed: 01/06/2023]
Abstract
Maternal immune activation (mIA) during pregnancy is hypothesised to disrupt offspring neurodevelopment and predispose offspring to neurodevelopmental disorders such as schizophrenia. Rodent models of mIA have explored possible mechanisms underlying this paradigm and provide a vital tool for preclinical research. However, a comprehensive analysis of the molecular changes that occur in mIA-models is lacking, hindering identification of robust clinical targets. This systematic review assesses mIA-driven transcriptomic and epigenomic alterations in specific offspring brain regions. Across 118 studies, we focus on 88 candidate genes and show replicated changes in expression in critical functional areas, including elevated inflammatory markers, and reduced myelin and GABAergic signalling proteins. Further, disturbed epigenetic markers at nine of these genes support mIA-driven epigenetic modulation of transcription. Overall, our results demonstrate that current outcome measures have direct relevance for the hypothesised pathology of schizophrenia and emphasise the importance of mIA-models in contributing to the understanding of biological pathways impacted by mIA and the discovery of new drug targets.
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Affiliation(s)
- Rebecca M Woods
- Division of Evolution & Genomic Sciences, School of Biological Sciences, Manchester Academic Health Science Center, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PT, United Kingdom.
| | - Jarred M Lorusso
- Division of Evolution & Genomic Sciences, School of Biological Sciences, Manchester Academic Health Science Center, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| | - Harry G Potter
- Division of Evolution & Genomic Sciences, School of Biological Sciences, Manchester Academic Health Science Center, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| | - Joanna C Neill
- Division of Pharmacy & Optometry, School of Health Sciences, Manchester Academic Health Science Center, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PL, United Kingdom
| | - Jocelyn D Glazier
- Division of Evolution & Genomic Sciences, School of Biological Sciences, Manchester Academic Health Science Center, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| | - Reinmar Hager
- Division of Evolution & Genomic Sciences, School of Biological Sciences, Manchester Academic Health Science Center, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PT, United Kingdom
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49
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Romero-Miguel D, Casquero-Veiga M, MacDowell KS, Torres-Sanchez S, Garcia-Partida JA, Lamanna-Rama N, Romero-Miranda A, Berrocoso E, Leza JC, Desco M, Soto-Montenegro ML. A Characterization of the Effects of Minocycline Treatment During Adolescence on Structural, Metabolic, and Oxidative Stress Parameters in a Maternal Immune Stimulation Model of Neurodevelopmental Brain Disorders. Int J Neuropsychopharmacol 2021; 24:734-748. [PMID: 34165516 PMCID: PMC8453277 DOI: 10.1093/ijnp/pyab036] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 06/01/2021] [Accepted: 06/18/2021] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Minocycline (MIN) is a tetracycline with antioxidant, anti-inflammatory, and neuroprotective properties. Given the likely involvement of inflammation and oxidative stress (IOS) in schizophrenia, MIN has been proposed as a potential adjuvant treatment in this pathology. We tested an early therapeutic window, during adolescence, as prevention of the schizophrenia-related deficits in the maternal immune stimulation (MIS) animal model. METHODS On gestational day 15, Poly I:C or vehicle was injected in pregnant Wistar rats. A total 93 male offspring received MIN (30 mg/kg) or saline from postnatal day (PND) 35-49. At PND70, rats were submitted to the prepulse inhibition test. FDG-PET and T2-weighted MRI brain studies were performed at adulthood. IOS markers were evaluated in frozen brain tissue. RESULTS MIN treatment did not prevent prepulse inhibition test behavioral deficits in MIS offspring. However, MIN prevented morphometric abnormalities in the third ventricle but not in the hippocampus. Additionally, MIN reduced brain metabolism in cerebellum and increased it in nucleus accumbens. Finally, MIN reduced the expression of iNOS (prefrontal cortex, caudate-putamen) and increased the levels of KEAP1 (prefrontal cortex), HO1 and NQO1 (amygdala, hippocampus), and HO1 (caudate-putamen). CONCLUSIONS MIN treatment during adolescence partially counteracts volumetric abnormalities and IOS deficits in the MIS model, likely via iNOS and Nrf2-ARE pathways, also increasing the expression of cytoprotective enzymes. However, MIN treatment during this peripubertal stage does not prevent sensorimotor gating deficits. Therefore, even though it does not prevent all the MIS-derived abnormalities evaluated, our results suggest the potential utility of early treatment with MIN in other schizophrenia domains.
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Affiliation(s)
| | - Marta Casquero-Veiga
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain,CIBER de Salud Mental (CIBERSAM), Madrid, Spain
| | - Karina S MacDowell
- CIBER de Salud Mental (CIBERSAM), Madrid, Spain,Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense (UCM), IIS Imas12, IUIN, Madrid, Spain
| | - Sonia Torres-Sanchez
- CIBER de Salud Mental (CIBERSAM), Madrid, Spain,Neuropsychopharmacology and Psychobiology Research Group, Psychobiology Area, Department of Psychology, Universidad de Cádiz, Puerto Real (Cádiz), Spain,Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain
| | - José Antonio Garcia-Partida
- CIBER de Salud Mental (CIBERSAM), Madrid, Spain,Neuropsychopharmacology and Psychobiology Research Group, Psychobiology Area, Department of Psychology, Universidad de Cádiz, Puerto Real (Cádiz), Spain,Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain
| | | | | | - Esther Berrocoso
- CIBER de Salud Mental (CIBERSAM), Madrid, Spain,Neuropsychopharmacology and Psychobiology Research Group, Psychobiology Area, Department of Psychology, Universidad de Cádiz, Puerto Real (Cádiz), Spain,Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain
| | - Juan C Leza
- CIBER de Salud Mental (CIBERSAM), Madrid, Spain,Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense (UCM), IIS Imas12, IUIN, Madrid, Spain
| | - Manuel Desco
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain,CIBER de Salud Mental (CIBERSAM), Madrid, Spain,Departamento de Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III de Madrid, Leganés, Spain,Centro Nacional de Investigaciones Cardiovasculares, CNIC, Madrid, Spain,Correspondence: Manuel Desco, PhD, Laboratorio de Imagen Médica, Unidad de Medicina y Cirugía Experimental, Hospital General Universitario Gregorio Marañón, Dr. Esquerdo, 46. E-28007 Madrid, Spain ()
| | - María Luisa Soto-Montenegro
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain,CIBER de Salud Mental (CIBERSAM), Madrid, Spain,High Performance Research Group in Physiopathology and Pharmacology of the Digestive System (NeuGut), University Rey Juan Carlos (URJC), Alcorcón, Spain
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Haan N, Westacott LJ, Carter J, Owen MJ, Gray WP, Hall J, Wilkinson LS. Haploinsufficiency of the schizophrenia and autism risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms. Transl Psychiatry 2021; 11:313. [PMID: 34031371 PMCID: PMC8144403 DOI: 10.1038/s41398-021-01415-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 04/21/2021] [Accepted: 05/04/2021] [Indexed: 12/12/2022] Open
Abstract
Genetic risk factors can significantly increase chances of developing psychiatric disorders, but the underlying biological processes through which this risk is effected remain largely unknown. Here we show that haploinsufficiency of Cyfip1, a candidate risk gene present in the pathogenic 15q11.2(BP1-BP2) deletion may impact on psychopathology via abnormalities in cell survival and migration of newborn neurons during postnatal hippocampal neurogenesis. We demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult-born hippocampal neurons due to reduced apoptosis, without altering proliferation. We show this is due to a cell autonomous failure of microglia to induce apoptosis through the secretion of the appropriate factors, a previously undescribed mechanism. Furthermore, we show an abnormal migration of adult-born neurons due to altered Arp2/3 mediated actin dynamics. Together, our findings throw new light on how the genetic risk candidate Cyfip1 may influence the hippocampus, a brain region with strong evidence for involvement in psychopathology.
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Affiliation(s)
- Niels Haan
- Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, UK.
| | - Laura J Westacott
- Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, UK
| | - Jenny Carter
- Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, UK
| | - Michael J Owen
- Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, UK
| | - William P Gray
- Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, UK
- Brain Repair and Intercranial Neurotherapeutics Unit, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, UK
- Hodge Centre for Neuropsychiatric Immunology, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, UK
| | - Jeremy Hall
- Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, UK
- Hodge Centre for Neuropsychiatric Immunology, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, UK
| | - Lawrence S Wilkinson
- Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, UK
- Hodge Centre for Neuropsychiatric Immunology, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, UK
- School of Psychology, Cardiff University, Tower Building, Cardiff, UK
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