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Petrovick M, Shcherbina A, Farina EK, Thompson LA, Niro PJ, McClung JP, Lieberman HR. The minor allele of the serotonin transporter gene variant rs4251417 is associated with increased resilience in soldiers experiencing acute stress during survival training: preliminary findings. ANXIETY, STRESS, AND COPING 2025; 38:161-180. [PMID: 39165169 DOI: 10.1080/10615806.2024.2388850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 07/26/2024] [Accepted: 07/30/2024] [Indexed: 08/22/2024]
Abstract
BACKGROUND Variation in cognitive, emotional and physical performance in response to stress is attributable to environmental and genetic factors. Ability to adapt to stress is resilience. OBJECTIVES This study investigated genetic factors associated with resilience in soldiers exposed to severe stress due to intense physical and mental demands at Survive, Evade, Resist and Escape school, a unique environment to study acute stress and resiliency in real-world circumstances. DESIGN A preliminary correlational study was conducted to identify genetic markers for resilience to stress. METHODS Mood state, resiliency and dissociative state of 73 soldiers were assessed using: Connor-Davidson Resilience Scale (CD-RISC); Profile of Mood States (POMS); and Clinician-Administered Dissociative States Scale (CADSS). Change scores for resilience-related stress markers were computed; 116 single nucleotide polymorphisms (SNPs) associated with stress, depression, anxiety, sleep, or psychiatric disorders were assessed. RESULTS A significant association between change in CD-RISC score and SNP rs4251417, present in an intron of SLC6A4, the serotonin transporter gene, was observed. CONCLUSIONS Individuals with the minor allele of SNP rs4251417 had a greater positive change in CD-RISC, indicating increased self-assessed resilience. This study suggests the minor allele of SNP rs4251417 of SLC6A4 is associated with resilience when individuals are exposed to high stress.
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Affiliation(s)
- Martha Petrovick
- Biological & Chemical Technologies, MIT Lincoln Laboratory, Lexington, MA, USA
| | - Anna Shcherbina
- Biological & Chemical Technologies, MIT Lincoln Laboratory, Lexington, MA, USA
| | - Emily K Farina
- Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA
| | - Lauren A Thompson
- Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA
| | - Philip J Niro
- Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA
| | - James P McClung
- Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA
| | - Harris R Lieberman
- Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA
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Tao Y, Wang L, Ye X, Qian X, Pan D, Dong X, Jiang Q, Hu P. Huang Qin decoction increases SLC6A4 expression and blocks the NFκB-mediated NLRP3/Caspase1/GSDMD pathway to disrupt colitis-associated carcinogenesis. Funct Integr Genomics 2024; 24:55. [PMID: 38467948 PMCID: PMC10927794 DOI: 10.1007/s10142-024-01334-x] [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: 11/29/2023] [Revised: 01/23/2024] [Accepted: 03/04/2024] [Indexed: 03/13/2024]
Abstract
Huang Qin decoction (HQD) is a traditional Chinese medicine formula for treating colitis, but the effects and molecular mechanism of action of HQD in colitis-associated carcinogenesis (CAC) are still unclear. Therefore, we aimed to determine the beneficial effects of HQD on CAC in mice and to reveal the underlying mechanism involved. AOM/DSS was used to induce CAC in mice, and the effects of HQD on tumorigenesis in mice were examined (with mesalazine serving as a positive control). Mesalazine or HQD treatment alleviated body weight loss and decreased the disease activity index in mice induced by AOM/DSS. Mesalazine or HQD treatment also suppressed the shortening of colon tissue length, the number of tumors, and the infiltration of inflammatory cells. The genes targeted by HQD were predicted and verified, followed by knockout experiments. Elevated SLC6A4 and inhibited serotonin production and inflammation were observed in HQD-treated mice. HQD inhibited the NFκB and NLRP3/caspase1/GSDMD pathways. The therapeutic effect of HQD was diminished in SLC6A4-deficient AOM/DSS mice. Additionally, the downregulation of SLC6A4 mitigated the inhibitory effect of HQD-containing serum on MODE-K cell pyroptosis. Our findings suggest that SLC6A4 is a pivotal regulator of HQD-alleviated CAC via its modulation of the NLRP3/caspase1/GSDMD pathway.
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Affiliation(s)
- Yili Tao
- Department of Gastroenterology, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, 213000, Jiangsu, P.R. China
| | - Lai Wang
- Department of Gastroenterology, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, 213000, Jiangsu, P.R. China
| | - Xiaofeng Ye
- Department of Gastroenterology, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, 213000, Jiangsu, P.R. China
| | - Xin Qian
- Department of Gastroenterology, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, 213000, Jiangsu, P.R. China
| | - Danye Pan
- Department of Gastroenterology, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, 213000, Jiangsu, P.R. China
| | - Xiaoyu Dong
- Department of Gastroenterology, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, 213000, Jiangsu, P.R. China
| | - Qian Jiang
- Digestive Disease Diagnosis and Treatment Center of Integrated Traditional Chinese and Western Medicine, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, 213000, Jiangsu, P.R. China
| | - Po Hu
- Department of Pulmonary Diseases, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, 213000, Jiangsu, P.R. China.
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Zhang Z, Yang Y, Kong W, Huang S, Tan Y, Huang S, Zhang M, Lu H, Li Y, Li X, Liu S, Wen Y, Shang D. A Bibliometric and Visual Analysis of Single Nucleotide Polymorphism Studies in Depression. Curr Neuropharmacol 2024; 22:302-322. [PMID: 37581520 PMCID: PMC10788886 DOI: 10.2174/1570159x21666230815125430] [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: 10/23/2022] [Revised: 11/30/2022] [Accepted: 02/10/2023] [Indexed: 08/16/2023] Open
Abstract
BACKGROUND Genetic polymorphism has been proven to have an important association with depression, which can influence the risk of developing depression, the efficacy of medications, and adverse effects via metabolic and neurological pathways. Nonetheless, aspects of the association between single nucleotide polymorphisms and depression have not been systematically investigated by bibliometric analysis. OBJECTIVE The aim of this study was to analyze the current status and trends of single nucleotide polymorphism research on depression through bibliometric and visual analysis. METHODS The Web of Science Core Collection was used to retrieve 10,043 articles that were published between 1998 and 2021. CiteSpace (6.1 R4) was used to perform collaborative network analysis, co-citation analysis, co-occurrence analysis, and citation burst detection. RESULTS The most productive and co-cited journals were the Journal of Affective Disorders and Biological Psychiatry, respectively, and an analysis of the references showed that the most recent research focused on the largest thematic cluster, "5-HT", reflecting the important research base in this area. "CYP2D6" has been in the spotlight since its emergence in 2009 and has become a research hotspot since its outbreak in 2019. However, "BDNF ", "COMT ", "older adults", "loci", and "DNA methylation" are also the new frontier of research, and some of them are currently in the process of exploration. CONCLUSION These findings offer a useful perspective on existing research and potential future approaches in the study of the association between single nucleotide polymorphisms and depression, which may assist researchers in selecting appropriate collaborators or journals.
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Affiliation(s)
- Zi Zhang
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Ye Yang
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Wan Kong
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Shanqing Huang
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Yaqian Tan
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Shanshan Huang
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Ming Zhang
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Haoyang Lu
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Yuhua Li
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Xiaolin Li
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Shujing Liu
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Yuguan Wen
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Dewei Shang
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
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D'Acquisto F, D'Addario C, Cooper D, Pallanti S, Blacksell I. Peripheral control of psychiatric disorders: Focus on OCD. Are we there yet? Compr Psychiatry 2023; 123:152388. [PMID: 37060625 DOI: 10.1016/j.comppsych.2023.152388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 12/13/2022] [Accepted: 04/04/2023] [Indexed: 04/17/2023] Open
Abstract
"We are all in this together" - we often hear this phrase when we want to flag up a problem that is not for a single individual but concerns us all. A similar reflection has been recently made in the field of mental disorders where brain-centric scientists have started to zoom out their brain-focused graphical representations of the mechanisms regulating psychiatric diseases to include other organs or mediators that did not belong historically to the world of neuroscience. The brain itself - that has long been seen as a master in command secluded in its fortress (the blood brain barrier), has now become a collection of Airbnb(s) where all sorts of cells come in and out and sometimes even rearrange the furniture! Under this new framework of reference, mental disorders have become multisystem pathologies where different biological systems - not just the CNS -contribute 'all together' to the development and severity of the disease. In this narrative review article, we will focus on one of the most popular biological systems that has been shown to influence the functioning of the CNS: the immune system. We will specifically highlight the two main features of the immune system and the CNS that we think are important in the context of mental disorders: plasticity and memory.
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Affiliation(s)
- Fulvio D'Acquisto
- School of Life and Health Science, University of Roehampton, London, UK.
| | - Claudio D'Addario
- Faculty of Bioscience, University of Teramo, Teramo, Italy; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Dianne Cooper
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Stefano Pallanti
- Albert Einstein College of Medicine,New York, USA; Istituto di Neuroscienze, Florence, Italy
| | - Isobel Blacksell
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Franzago M, Orecchini E, Porreca A, Mondanelli G, Orabona C, Dalla Ragione L, Di Nicola M, Stuppia L, Vitacolonna E, Beccari T, Ceccarini MR. SLC6A4 DNA Methylation Levels and Serum Kynurenine/Tryptophan Ratio in Eating Disorders: A Possible Link with Psychopathological Traits? Nutrients 2023; 15:nu15020406. [PMID: 36678277 PMCID: PMC9866524 DOI: 10.3390/nu15020406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/07/2023] [Accepted: 01/11/2023] [Indexed: 01/15/2023] Open
Abstract
Background: The incidence of eating disorders (EDs), serious mental and physical conditions characterized by a disturbance in eating or eating-related behaviors, has increased steadily. The present study aims to develop insights into the pathophysiology of EDs, spanning over biochemical, epigenetic, psychopathological, and clinical data. In particular, we focused our attention on the relationship between (i) DNA methylation profiles at promoter-associated CpG sites of the SCL6A4 gene, (ii) serum kynurenine/tryptophan levels and ratio (Kyn/Trp), and (iii) psychopathological traits in a cohort of ED patients. Among these, 45 patients were affected by restricting anorexia nervosa (AN0), 21 by purging AN (AN1), 21 by bulimia (BN), 31 by binge eating disorders (BED), 23 by unspecified feeding or eating disorders (UFED), and finally 14 by other specified eating disorders (OSFED) were compared to 34 healthy controls (CTRs). Results: Kyn level was higher in BED, UFED, and OSFED compared to CTRs (p ≤ 0.001). On the other hand, AN0, AN1, and BN patients showed significatively lower Kyn levels compared to the other three ED groups but were closed to CTRs. Trp was significantly higher in AN0, AN1, and BN in comparison to other ED groups. Moreover, AN1 and BN showed more relevant Trp levels than CTRs (p <0.001). BED patients showed a lower Trp as compared with CTRs (p ≤ 0.001). In addition, Kyn/Trp ratio was lower in the AN1 subtype but higher in BED, UFED, and OSFED patients than in CTRs (p ≤ 0.001). SCL6A4 DNA methylation level at CpG5 was lower in AN0 compared to BED (p = 0.021), and the CpG6 methylation was also significantly lower in AN0 in comparison to CTRs (p = 0.025). The mean methylation levels of the six CpGs analyzed were lower only in the AN0 subgroup compared to CTRs (p = 0.008). Relevant psychological trait EDI-3 subscales were correlated with biochemical and epigenetic data. Conclusions: These findings underline the complexity of psychological and pathophysiological components of EDs.
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Affiliation(s)
- Marica Franzago
- Department of Medicine and Aging, School of Medicine and Health Sciences, “G. d’Annunzio” University, 66100 Chieti, Italy
- Center for Advanced Studies and Technology, “G. d’Annunzio” University, 66100 Chieti, Italy
| | - Elena Orecchini
- Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy
| | - Annamaria Porreca
- Laboratory of Biostatistics, Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University, 66100 Chieti, Italy
| | - Giada Mondanelli
- Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy
| | - Ciriana Orabona
- Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy
| | - Laura Dalla Ragione
- Food Science and Human Nutrition Unit, University Campus Biomedico of Rome, 00128 Rome, Italy
| | - Marta Di Nicola
- Laboratory of Biostatistics, Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University, 66100 Chieti, Italy
| | - Liborio Stuppia
- Center for Advanced Studies and Technology, “G. d’Annunzio” University, 66100 Chieti, Italy
- Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, “G. d’Annunzio” University, 66100 Chieti, Italy
| | - Ester Vitacolonna
- Department of Medicine and Aging, School of Medicine and Health Sciences, “G. d’Annunzio” University, 66100 Chieti, Italy
- Center for Advanced Studies and Technology, “G. d’Annunzio” University, 66100 Chieti, Italy
| | - Tommaso Beccari
- Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy
| | - Maria Rachele Ceccarini
- Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy
- Correspondence: ; Tel.: +39-075-585-7905
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Castillero E, Fitzpatrick E, Keeney SJ, D’Angelo AM, Pressly BB, Simpson MT, Kurade M, Erwin WC, Moreno V, Camillo C, Shukla HJ, Inamdar VV, Aghali A, Grau JB, Salvati E, Nissim I, Rauova L, Oyama MA, Stachelek SJ, Brown C, Krieger AM, Levy RJ, Ferrari G. Decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation. Sci Transl Med 2023; 15:eadc9606. [PMID: 36599005 PMCID: PMC9896655 DOI: 10.1126/scitranslmed.adc9606] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. Here, we show that a decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR. Through studies of a population of patients with MR, we show that selective serotonin reuptake inhibitor (SSRI) use and SERT promoter polymorphism 5-HTTLPR LL genotype were associated with MV surgery at younger age. Functional characterization of 122 human MV samples, in conjunction with in vivo studies in SERT-/- mice and wild-type mice treated with the SSRI fluoxetine, showed that diminished SERT activity in MV interstitial cells (MVICs) contributed to the pathophysiology of MR through enhanced serotonin receptor (HTR) signaling. SERT activity was decreased in LL MVICs partially because of diminished membrane localization of SERT. In mice, fluoxetine treatment or SERT knockdown resulted in thickened MV leaflets. Similarly, silencing of SERT in normal human MVICs led to up-regulation of transforming growth factor β1 (TGFβ1) and collagen (COL1A1) in the presence of serotonin. In addition, treatment of MVICs with fluoxetine not only directly inhibited SERT activity but also decreased SERT expression and increased HTR2B expression. Fluoxetine treatment and LL genotype were also associated with increased COL1A1 expression in the presence of serotonin in MVICs, and these effects were attenuated by HTR2B inhibition. These results suggest that assessment of both 5-HTTLPR genotype and SERT-inhibiting treatments may be useful tools to risk-stratify patients with MV disease to estimate the likelihood of rapid disease progression.
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Affiliation(s)
- Estibaliz Castillero
- Department of Surgery, Columbia University; New York, NY, 10032, USA.,Corresponding author. (G.F.), (E.C.)
| | - Emmett Fitzpatrick
- The Pediatric Heart Valve Center, and the Division of Cardiology, The Children’s Hospital of Philadelphia; Philadelphia, PA, 19104, USA
| | - Samuel J. Keeney
- The Pediatric Heart Valve Center, and the Division of Cardiology, The Children’s Hospital of Philadelphia; Philadelphia, PA, 19104, USA
| | - Alex M. D’Angelo
- Department of Surgery, Columbia University; New York, NY, 10032, USA
| | - Benjamin B. Pressly
- The Pediatric Heart Valve Center, and the Division of Cardiology, The Children’s Hospital of Philadelphia; Philadelphia, PA, 19104, USA
| | | | - Mangesh Kurade
- Department of Surgery, Columbia University; New York, NY, 10032, USA
| | - W. Clinton Erwin
- Department of Surgery, Columbia University; New York, NY, 10032, USA
| | - Vivian Moreno
- Department of Surgery, Columbia University; New York, NY, 10032, USA
| | - Chiara Camillo
- Department of Surgery, Columbia University; New York, NY, 10032, USA
| | - Halley J. Shukla
- The Pediatric Heart Valve Center, and the Division of Cardiology, The Children’s Hospital of Philadelphia; Philadelphia, PA, 19104, USA
| | - Vaishali V. Inamdar
- The Pediatric Heart Valve Center, and the Division of Cardiology, The Children’s Hospital of Philadelphia; Philadelphia, PA, 19104, USA
| | - Arbi Aghali
- The Pediatric Heart Valve Center, and the Division of Cardiology, The Children’s Hospital of Philadelphia; Philadelphia, PA, 19104, USA
| | - Juan B. Grau
- Valley Hospital Heart Institute; Ridgewood, NJ, 07450, USA
| | - Elisa Salvati
- The Pediatric Heart Valve Center, and the Division of Cardiology, The Children’s Hospital of Philadelphia; Philadelphia, PA, 19104, USA
| | - Itzhak Nissim
- Division of Human Genetics and Metabolic Disease, Children’s Hospital of Philadelphia; Philadelphia, PA, 19104, USA.,Department of Pediatrics, Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA, 19104, USA
| | - Lubica Rauova
- Division of Hematology, The Children’s Hospital of Philadelphia; Philadelphia, PA, 19104, USA
| | - Mark A. Oyama
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania; Philadelphia, PA, 19104, USA
| | - Stanley J. Stachelek
- The Pediatric Heart Valve Center, and the Division of Cardiology, The Children’s Hospital of Philadelphia; Philadelphia, PA, 19104, USA
| | - Chase Brown
- Department of Surgery, University of Pennsylvania, Smilow Center for Translational Research; Philadelphia, PA 19104, USA
| | - Abba M. Krieger
- Statistics Department, The Wharton School, University of Pennsylvania; Philadelphia, PA 19104, USA
| | - Robert J. Levy
- The Pediatric Heart Valve Center, and the Division of Cardiology, The Children’s Hospital of Philadelphia; Philadelphia, PA, 19104, USA
| | - Giovanni Ferrari
- Department of Surgery, Columbia University; New York, NY, 10032, USA.,Department of Biomedical Engineering, Columbia University; New York, NY, 10027, USA.,Corresponding author. (G.F.), (E.C.)
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González Delgado S, Garza-Veloz I, Trejo-Vazquez F, Martinez-Fierro ML. Interplay between Serotonin, Immune Response, and Intestinal Dysbiosis in Inflammatory Bowel Disease. Int J Mol Sci 2022; 23:ijms232415632. [PMID: 36555276 PMCID: PMC9779345 DOI: 10.3390/ijms232415632] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/05/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is a chronic gastrointestinal disorder characterized by periods of activity and remission. IBD includes Crohn's disease (CD) and ulcerative colitis (UC), and even though IBD has not been considered as a heritable disease, there are genetic variants associated with increased risk for the disease. 5-Hydroxytriptamine (5-HT), or serotonin, exerts a wide range of gastrointestinal effects under both normal and pathological conditions. Furthermore, Serotonin Transporter (SERT) coded by Solute Carrier Family 6 Member 4 (SLC6A4) gene (located in the 17q11.1-q12 chromosome), possesses genetic variants, such as Serotonin Transporter Gene Variable Number Tandem Repeat in Intron 2 (STin2-VNTR) and Serotonin-Transporter-linked promoter region (5-HTTLPR), which have an influence over the functionality of SERT in the re-uptake and bioavailability of serotonin. The intestinal microbiota is a crucial actor in normal human gut physiology, exerting effects on serotonin, SERT function, and inflammatory processes. As a consequence of abnormal serotonin signaling and SERT function under these inflammatory processes, the use of selective serotonin re-uptake inhibitors (SSRIs) has been seen to improve disease activity and extraintestinal manifestations, such as depression and anxiety. The aim of this study is to integrate scientific data linking the intestinal microbiota as a regulator of gut serotonin signaling and re-uptake, as well as its role in the pathogenesis of IBD. We performed a narrative review, including a literature search in the PubMed database of both review and original articles (no date restriction), as well as information about the SLC6A4 gene and its genetic variants obtained from the Ensembl website. Scientific evidence from in vitro, in vivo, and clinical trials regarding the use of selective serotonin reuptake inhibitors as an adjuvant therapy in patients with IBD is also discussed. A total of 194 articles were used between reviews, in vivo, in vitro studies, and clinical trials.
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Perić M, Bečeheli I, Čičin-Šain L, Desoye G, Štefulj J. Serotonin system in the human placenta - the knowns and unknowns. Front Endocrinol (Lausanne) 2022; 13:1061317. [PMID: 36531448 PMCID: PMC9751904 DOI: 10.3389/fendo.2022.1061317] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 11/10/2022] [Indexed: 12/02/2022] Open
Abstract
The biogenic monoamine serotonin (5-hydroxytryptamine, 5-HT) is a chemical messenger widely distributed in the brain and various other organs. Its homeostasis is maintained by the coordinated activity of a variety of proteins, including enzymes of serotonin metabolism, transmembrane transporters of serotonin, and serotonin receptors. The serotonin system has been identified also in the placenta in rodent models as a key component of placental physiology. However, serotonin pathways in the human placenta are far from well understood. Their alterations may have long-lasting consequences for the fetus that can manifest later in life. In this review, we summarize information on the location of the components of the serotonin system in the human placenta, their regulation, function, and alterations in pathological pregnancies. We highlight current controversies and discuss important topics for future research.
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Affiliation(s)
- Maja Perić
- Laboratory of Neurochemistry and Molecular Neurobiology, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
| | - Ivona Bečeheli
- Laboratory of Neurochemistry and Molecular Neurobiology, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
| | - Lipa Čičin-Šain
- Laboratory of Neurochemistry and Molecular Neurobiology, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
| | - Gernot Desoye
- Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria
| | - Jasminka Štefulj
- Laboratory of Neurochemistry and Molecular Neurobiology, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
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Investigation of the Serotonergic Activity and the Serotonin Content in Serum and Platelet, and the Possible Role of the Serotonin Transporter in Patients with Depression. Behav Sci (Basel) 2022; 12:bs12060178. [PMID: 35735388 PMCID: PMC9220674 DOI: 10.3390/bs12060178] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/19/2022] [Accepted: 05/31/2022] [Indexed: 02/05/2023] Open
Abstract
According to the monoamine hypothesis, the development of depression is associated with dysfunctions of the serotonergic system. Alterations in the serotonin transporter gene (5-HTTLPR), the serotonergic activity in the brain, and the content of serotonin (5-HT) have been related to depression and were examined separately by previous studies. This study investigates these parameters in 89 depressed patients and 89 healthy participants. We investigated the serotonergic activity measured by the loudness dependence of auditory evoked potentials (LDAEP). In addition to the examination of the serotonin content (serum and platelet), enzyme-linked immunosorbent assays (ELISA) were used and 5-HTTLPR genotypes were analyzed. We observed a lower serotonin content in patients compared to healthy participants. Further, we noticed a correlation between anxiety and depression-associated symptoms with serotonergic activity. Patients treated with SSRI/SNRI showed decreased contents of serum serotonin compared to patients without any psychotropic medication or other psychotropic medications. Since the serotonergic activity, peripheral serotonin content, and 5-HTTLPR were unrelated, the results suggest independent alterations of central and peripheral serotonergic systems in depression. In line with this finding, serotonergic activity was related to anxiety and depression symptoms. Furthermore, the applied medication seems to influence serum serotonin content in patients with depression.
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Kamran M, Bibi F, ur. Rehman A, Morris DW. Major Depressive Disorder: Existing Hypotheses about Pathophysiological Mechanisms and New Genetic Findings. Genes (Basel) 2022; 13:646. [PMID: 35456452 PMCID: PMC9025468 DOI: 10.3390/genes13040646] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/16/2022] [Accepted: 03/23/2022] [Indexed: 01/08/2023] Open
Abstract
Major depressive disorder (MDD) is a common mental disorder generally characterized by symptoms associated with mood, pleasure and effectiveness in daily life activities. MDD is ranked as a major contributor to worldwide disability. The complex pathogenesis of MDD is not yet understood, and this is a major cause of failure to develop new therapies and MDD recurrence. Here we summarize the literature on existing hypotheses about the pathophysiological mechanisms of MDD. We describe the different approaches undertaken to understand the molecular mechanism of MDD using genetic data. Hundreds of loci have now been identified by large genome-wide association studies (GWAS). We describe these studies and how they have provided information on the biological processes, cell types, tissues and druggable targets that are enriched for MDD risk genes. We detail our understanding of the genetic correlations and causal relationships between MDD and many psychiatric and non-psychiatric disorders and traits. We highlight the challenges associated with genetic studies, including the complexity of MDD genetics in diverse populations and the need for a study of rare variants and new studies of gene-environment interactions.
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Affiliation(s)
- Muhammad Kamran
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan; (M.K.); (A.u.R.)
- Centre for Neuroimaging, Cognition and Genomics (NICOG), Discipline of Biochemistry, National University of Ireland Galway, H91 CF50 Galway, Ireland
| | - Farhana Bibi
- Department of Microbiology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan;
| | - Asim. ur. Rehman
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan; (M.K.); (A.u.R.)
| | - Derek W. Morris
- Centre for Neuroimaging, Cognition and Genomics (NICOG), Discipline of Biochemistry, National University of Ireland Galway, H91 CF50 Galway, Ireland
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11
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Huang Y, Gao J, Gao P, Peng D, Dai Y, Jiang H, Zhang X. A comprehensive assessment of genetic variation in serotonin transporter gene (5-HTTLPR+rs25531) and the response to dapoxetine in Chinese patients with premature ejaculation. Andrologia 2021; 53:e14141. [PMID: 34118072 DOI: 10.1111/and.14141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/13/2021] [Accepted: 05/21/2021] [Indexed: 11/29/2022] Open
Abstract
This study was to explore whether serotonin transporter gene-linked polymorphic region polymorphisms (5-HTTLPR+rs25531) influence the response to dapoxetine treatment in a Chinese population with premature ejaculation (PE). 112 patients with PE re-enrolled from our previous study received dapoxetine monotherapy. At the endpoint, patients with S'S' had a significant increased risk of nonresponse compared with L' carriers (p < .001). The improvement in S'S' genotype was significantly lower in premature ejaculation profile (PEP) items of 'control over ejaculation' (p = .035) and 'distress related to ejaculation' (p = .017) than that in L' carriers. As to clinical global impression of change (CGIC), results in S'S' subjects showed significantly lower scores (p = .008) and a less satisfaction rate reporting at least 'better' (p = .020) compared with L' carriers. Moreover, our findings suggested that patients with S'S' were more likely to develop adverse effects (AEs) compared with L' carriers (p = .040). This study suggests that PE patients bearing the S'S' genotype have an inferior comprehensive efficacy and safety of dapoxetine treatment, which consist of poorer response in IELTs, less improvement in patient-reported outcome (PRO) measures and greater incidence of AEs, than L' carriers. Variants of triallelic 5-HTTLPR may play a major role as a predictor of treatment response to dapoxetine.
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Affiliation(s)
- Yuanyuan Huang
- Department of Urology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jingjing Gao
- Department of Urology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Pan Gao
- Department of Urology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Dangwei Peng
- Department of Urology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yutian Dai
- Department of Andrology, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Hui Jiang
- Department of Andrology, Peking University Third Hospital, Beijing, China.,Department of Human Sperm Bank, Peking University Third Hospital, Beijing, China
| | - Xiansheng Zhang
- Department of Urology, First Affiliated Hospital of Anhui Medical University, Hefei, China
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12
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Stilley SE, Blakely RD. Rare Opportunities for Insights Into Serotonergic Contributions to Brain and Bowel Disorders: Studies of the SERT Ala56 Mouse. Front Cell Neurosci 2021; 15:677563. [PMID: 34149362 PMCID: PMC8210832 DOI: 10.3389/fncel.2021.677563] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022] Open
Abstract
Altered structure, expression, and regulation of the presynaptic serotonin (5-HT) transporter (SERT) have been associated with multiple neurobehavioral disorders, including mood disorders, obsessive-compulsive disorder (OCD), and autism spectrum disorder (ASD). Opportunities to investigate mechanistic links supporting these associations were spurred with the identification of multiple, rare human SERT coding variants in a study that established a male-specific linkage of ASD to a linkage marker on chromosome 17 which encompassed the location of the SERT gene (SLC6A4). We have explored the most common of these variants, SERT Ala56, in vitro and in vivo. Results support a tonic elevation of 5-HT transport activity in transfected cells and human lymphoblasts by the variant in vitro that leads to an increased 5-HT clearance rate in vivo when studied in the SERT Ala56 mouse model, along with altered sensitivity to SERT regulatory signaling pathways. Importantly, hyperserotonemia, or an elevated whole blood 5-HT, level, was found in SERT Ala56 mice, reproducing a well-replicated trait observed in a significant fraction of ASD subjects. Additionally, we found multiple biochemical, physiological, and behavioral alterations in the SERT Ala56 mice that can be analogized to those observed in ASD and its medical comorbidities. The similarity of the functional impact of the SERT Ala56 variant to the consequences of p38α MAPK activation, ascribed to the induction of a biased conformation of the transporter toward an outward-facing conformation, has resulted in successful efforts to restore normal behavioral and bowel function via pharmacological and genetic p38α MAPK targeting. Moreover, the ability of the inflammatory cytokine IL-1β to enhance SERT activity via a p38α MAPK-dependent pathway suggests that the SERT Ala56 conformation mimics that of a chronic inflammatory state, supporting findings in ASD of elevated inflammatory cytokine levels. In this report, we review studies of the SERT Ala56 variant, discussing opportunities for continued insight into how chronically altered synaptic 5-HT homeostasis can drive reversible, functional perturbations in 5-HT sensitive pathways in the brain and periphery, and how targeting the SERT regulome, particularly through activating pathways such as those involving IL-1β/p38α MAPK, may be of benefit for neurobehavioral disorders, including ASD.
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Affiliation(s)
- Samantha E. Stilley
- Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, United States
| | - Randy D. Blakely
- Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, United States
- Brain Institute, Florida Atlantic University, Jupiter, FL, United States
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13
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Feng K, Liu Y, Sun J, Zhao C, Duan Y, Wang W, Yan K, Yan X, Sun H, Hu Y, Han J. Compound Danshen Dripping Pill inhibits doxorubicin or isoproterenol-induced cardiotoxicity. Biomed Pharmacother 2021; 138:111531. [PMID: 34311530 DOI: 10.1016/j.biopha.2021.111531] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/19/2021] [Accepted: 03/21/2021] [Indexed: 12/11/2022] Open
Abstract
Heart failure (HF) is the advanced heart disease with high morbidity and mortality. Compound DanShen Dripping Pill (CDDP) is a widely used Traditional Chinese Medicine for cardiovascular disease treatment. Herein, we investigated if CDDP can protect mice against doxorubicin (DOX) or isoprenaline (ISO)-induced HF. After 3 days feeding of normal chow containing CDDP, mice were started DOX or ISO treatment for 4 weeks or 18 days. At the end of treatment, mice were conducted electrocardiogram and echocardiographic test. Blood and heart samples were determined biochemical parameters, myocardial structure and expression of the related molecules. CDDP normalized DOX/ISO-induced heart weight changes, HF parameters and fibrogenesis. The DOX/ISO-impaired left ventricular ejection fraction and fractional shortening were restored by CDDP. Mechanistically, CDDP blocked DOX/ISO-inhibited expression of antioxidant enzymes and DOX/ISO-induced expression of pro-fibrotic molecules, inflammation and cell apoptosis. Additional DOX/ISO-impaired targets in cardiac function but protected by CDDP were identified by RNAseq, qRT-PCR and Western blot. In addition, CDDP protected cardiomyocytes against oxygen-glucose deprivation-induced injuries. Taken together, our study shows that CDDP can protect against myocardial injuries in different models, suggesting its potential application for HF treatment.
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Affiliation(s)
- Ke Feng
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Yuxin Liu
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Jia Sun
- GeneNet Pharmaceuticals Co. Ltd., Tianjin, China
| | - Chunlai Zhao
- GeneNet Pharmaceuticals Co. Ltd., Tianjin, China
| | - Yajun Duan
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei, China
| | - Wenjia Wang
- GeneNet Pharmaceuticals Co. Ltd., Tianjin, China
| | - Kaijing Yan
- GeneNet Pharmaceuticals Co. Ltd., Tianjin, China; The State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tasly Academy, Tasly Holding Group Co., Ltd, Tianjin, China; Tasly Pharmaceutical Group Co., Ltd, Tianjin, China
| | - Xijun Yan
- GeneNet Pharmaceuticals Co. Ltd., Tianjin, China; The State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tasly Academy, Tasly Holding Group Co., Ltd, Tianjin, China; Tasly Pharmaceutical Group Co., Ltd, Tianjin, China
| | - He Sun
- GeneNet Pharmaceuticals Co. Ltd., Tianjin, China; The State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tasly Academy, Tasly Holding Group Co., Ltd, Tianjin, China; Tasly Pharmaceutical Group Co., Ltd, Tianjin, China
| | - Yunhui Hu
- GeneNet Pharmaceuticals Co. Ltd., Tianjin, China.
| | - Jihong Han
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China.
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14
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Morningstar-Kywi N, Haworth IS, Mosley SA. Ligand-specific pharmacogenetic effects of nonsynonymous mutations. Pharmacogenet Genomics 2021; 31:75-82. [PMID: 33395026 DOI: 10.1097/fpc.0000000000000424] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
In pharmacogenomics, variable receptor phenotypes, resulting from genetic polymorphisms, are often described as a change in protein function or regulation observed upon exposure to a drug. However, in some instances, phenotypes are defined using a class of medications rather than individual drugs. This paradigm assumes that a variation associated with a drug response phenotype will retain the magnitude and direction of the effect for other drugs with the same mechanism of action. However, nonsynonymous polymorphisms may have ligand-specific effects. The purpose of this study was to investigate the potential for point mutations to asymmetrically affect the binding of different drugs to a common target. Ligand binding data from site-directed mutagenesis studies on five G-protein coupled receptors (beta-1 and -2 adrenergic, dopamine D2, angiotensin II and mu-opioid receptor) were collected and analyzed. Binding data from 81 studies for 253 ligands with 447 mutant proteins, including 10 naturally occurring human variants, were analyzed, yielding 1989 mutation-ligand pairs. Fold change in binding affinity for mutant proteins, relative to the wild-type, for different drugs was examined for ligand-specific effects, with a fold-change difference of one or more orders of magnitude between agents considered significant. Of the mutations examined, 49% were associated with ligand-specific effects. One human variant (T164I, beta-2 adrenergic receptor) showed ligand-specific effects for antiasthmatic agents. These results indicate that ligand-specific changes in binding are a possible consequence of missense mutations. This implies that caution needs to be exercised when grouping drugs together during design or interpretation of genotype-phenotype association studies.
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MESH Headings
- Angiotensin Receptor Antagonists/pharmacology
- Genetic Association Studies
- Humans
- Ligands
- Mutagenesis, Site-Directed
- Pharmacogenomic Testing
- Polymorphism, Genetic/genetics
- Receptors, Adrenergic, beta-1/genetics
- Receptors, Adrenergic, beta-2/genetics
- Receptors, Angiotensin/genetics
- Receptors, Dopamine D2/genetics
- Receptors, G-Protein-Coupled/antagonists & inhibitors
- Receptors, G-Protein-Coupled/genetics
- Receptors, Opioid, mu/antagonists & inhibitors
- Receptors, Opioid, mu/genetics
- Signal Transduction/drug effects
- Silent Mutation/genetics
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Affiliation(s)
| | - Ian S Haworth
- Departments of Pharmacology and Pharmaceutical Sciences
| | - Scott A Mosley
- Departments of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, California, USA
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15
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Bellia F, Vismara M, Annunzi E, Cifani C, Benatti B, Dell'Osso B, D'Addario C. Genetic and epigenetic architecture of Obsessive-Compulsive Disorder: In search of possible diagnostic and prognostic biomarkers. J Psychiatr Res 2021; 137:554-571. [PMID: 33213890 DOI: 10.1016/j.jpsychires.2020.10.040] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/25/2020] [Accepted: 10/28/2020] [Indexed: 02/07/2023]
Abstract
Obsessive-Compulsive Disorder (OCD) is a prevalent and severe clinical condition whose hallmarks are excessive, unwanted thoughts (obsessions) and repetitive behaviors (compulsions). The onset of symptoms generally occurs during pre-adult life and typically affects subjects in different aspects of their life's, compromising social and professional relationships. Although robust evidence suggests a genetic component in the etiopathogenesis of OCD, the causes of the disorder are still not completely understood. It is thus of relevance to take into account how genes interact with environmental risk factors, thought to be mediated by epigenetic mechanisms. We here provide an overview of genetic and epigenetic mechanisms of OCD, focusing on the modulation of key central nervous system genes, in the attempt to suggest possible disease biomarkers.
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Affiliation(s)
- Fabio Bellia
- Faculty of Bioscience, University of Teramo, Teramo, Italy
| | - Matteo Vismara
- Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milano, Italy
| | - Eugenia Annunzi
- Faculty of Bioscience, University of Teramo, Teramo, Italy; Department of Neuroscience, Imaging and Clinical Sciences, Gabriele D'Annunzio University, Chieti, Italy
| | - Carlo Cifani
- School of Pharmacy, University of Camerino, Camerino, Italy
| | - Beatrice Benatti
- Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milano, Italy; CRC "Aldo Ravelli", University of Milan, Milano, Italy
| | - Bernardo Dell'Osso
- Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milano, Italy; CRC "Aldo Ravelli", University of Milan, Milano, Italy; Department of Psychiatry and Behavioral Sciences, Stanford University, CA, USA.
| | - Claudio D'Addario
- Faculty of Bioscience, University of Teramo, Teramo, Italy; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
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16
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Beversdorf DQ, Shah A, Jhin A, Noel-MacDonnell J, Hecht P, Ferguson BJ, Bruce D, Tilley M, Talebizadeh Z. microRNAs and Gene-Environment Interactions in Autism: Effects of Prenatal Maternal Stress and the SERT Gene on Maternal microRNA Expression. Front Psychiatry 2021; 12:668577. [PMID: 34290629 PMCID: PMC8288023 DOI: 10.3389/fpsyt.2021.668577] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/24/2021] [Indexed: 12/16/2022] Open
Abstract
Background: Genetics and environment both are critical in autism spectrum disorder (ASD), but their interaction (G × E) is less understood. Numerous studies have shown higher incidence of stress exposures during pregnancies with children later diagnosed with ASD. However, many stress-exposed mothers have unaffected children. The serotonin transporter (SERT) gene affects stress reactivity. Two independent samples have shown that the association between maternal stress exposure and ASD is greatest with maternal presence of the SERT short (S)-allele (deletion in the promoter region). MicroRNAs play a regulatory role in the serotonergic pathway and in prenatal stress and are therefore potential mechanistic targets in this setting. Design/methods: We profiled microRNA expression in blood from mothers of children with ASD, with known stress exposure during pregnancy. Samples were divided into groups based on SERT genotypes (LL/LS/SS) and prenatal stress level (high/low). Results: Two thousand five hundred mature microRNAs were examined. The ANOVA analysis showed differential expression (DE) of 119 microRNAs; 90 were DE in high- vs. low-stress groups (stress-dependent). Two (miR-1224-5p, miR-331-3p) were recently reported by our group to exhibit stress-dependent expression in rodent brain samples from embryos exposed to prenatal stress. Another, miR-145-5p, is associated with maternal stress. Across SERT genotypes, with high stress exposure, 20 significantly DE microRNAs were detected, five were stress-dependent. These microRNAs may be candidates for stress × SERT genotype interactions. This is remarkable as these changes were from mothers several years after stress-exposed pregnancies. Conclusions: Our study provides evidence for epigenetic alterations in relation to a G × E model (prenatal maternal stress × SERT gene) in ASD.
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Affiliation(s)
- David Q Beversdorf
- Departments of Radiology, Neurology, and Psychological Sciences, William and Nancy Thompson Endowed Chair in Radiology, University of Missouri, Columbia, MO, United States.,Interdisciplinary Neuroscience Program, University of Missouri, Columbia, MO, United States
| | - Ayten Shah
- Children's Mercy Hospital, Kansas City, MO, United States
| | - Allison Jhin
- Kansas City University, Kansas City, MO, United States
| | - Janelle Noel-MacDonnell
- Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine, Kansas City, MO, United States
| | - Patrick Hecht
- Interdisciplinary Neuroscience Program, University of Missouri, Columbia, MO, United States
| | - Bradley J Ferguson
- Interdisciplinary Neuroscience Program, University of Missouri, Columbia, MO, United States.,Health Psychology, Radiology, and Thompson Center for Autism and Neurodevelopmental Disorders, University of Missouri, Columbia, MO, United States
| | - Danielle Bruce
- Department of Biology, Central Methodist University, Fayette, MO, United States
| | - Michael Tilley
- Department of Biology, Central Methodist University, Fayette, MO, United States
| | - Zohreh Talebizadeh
- Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine, Kansas City, MO, United States
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17
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Abstract
Precise control of monoamine neurotransmitter levels in the central nervous system (CNS) is crucial for proper brain function. Dysfunctional monoamine signaling is associated with several neuropsychiatric and neurodegenerative disorders. The plasma membrane monoamine transporter (PMAT) is a new polyspecific organic cation transporter encoded by the SLC29A4 gene. Capable of transporting monoamine neurotransmitters with low affinity and high capacity, PMAT represents a major uptake2 transporter in the brain. Broadly expressed in multiple brain regions, PMAT can complement the high-affinity, low-capacity monoamine uptake mediated by uptake1 transporters, the serotonin, dopamine, and norepinephrine transporters (SERT, DAT, and NET, respectively). This chapter provides an overview of the molecular and functional characteristics of PMAT together with its regional and cell-type specific expression in the mammalian brain. The physiological functions of PMAT in brain monoamine homeostasis are evaluated in light of its unique transport kinetics and brain location, and in comparison with uptake1 and other uptake2 transporters (e.g., OCT3) along with corroborating experimental evidences. Lastly, the possibility of PMAT's involvement in brain pathophysiological processes, such as autism, depression, and Parkinson's disease, is discussed in the context of disease pathology and potential link to aberrant monoamine pathways.
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18
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Ragu Varman D, Jayanthi LD, Ramamoorthy S. Glycogen synthase kinase-3ß supports serotonin transporter function and trafficking in a phosphorylation-dependent manner. J Neurochem 2020; 156:445-464. [PMID: 32797733 DOI: 10.1111/jnc.15152] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 07/23/2020] [Accepted: 08/10/2020] [Indexed: 12/13/2022]
Abstract
Serotonin (5-HT) transporter (SERT) plays a crucial role in serotonergic transmission in the central nervous system, and any aberration causes serious mental illnesses. Nevertheless, the cellular mechanisms that regulate SERT function and trafficking are not entirely understood. Growing evidence suggests that several protein kinases act as modulators. Here, we delineate the molecular mechanisms by which glycogen synthase kinase-3ß (GSK3ß) regulates SERT. When mouse striatal synaptosomes were treated with the GSK3α/ß inhibitor CHIR99021, we observed a significant increase in SERT function, Vmax , surface expression with a reduction in 5-HT Km and SERT phosphorylation. To further study how the SERT molecule is affected by GSK3α/ß, we used HEK-293 cells as a heterologous expression system. As in striatal synaptosomes, CHIR99021 treatment of cells expressing wild-type hSERT (hSERT-WT) resulted in a time and dose-dependent elevation of hSERT function with a concomitant increase in the Vmax and surface transporters because of reduced internalization and enhanced membrane insertion; silencing GSK3α/ß in these cells with siRNA also similarly affected hSERT. Converting putative GSK3α/ß phosphorylation site serine at position 48 to alanine in hSERT (hSERT-S48A) completely abrogated the effects of both the inhibitor CHIR99021 and GSK3α/ß siRNA. Substantiating these findings, over-expression of constitutively active GSK3ß with hSERT-WT, but not with hSERT-S48A, reduced SERT function, Vmax , surface density, and enhanced transporter phosphorylation. Both hSERT-WT and hSERT-S48A were inhibited similarly by PKC activation or by inhibition of Akt, CaMKII, p38 MAPK, or Src kinase. These findings provide new evidence that GSK3ß supports basal SERT function and trafficking via serine-48 phosphorylation.
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Affiliation(s)
- Durairaj Ragu Varman
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
| | - Lankupalle D Jayanthi
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
| | - Sammanda Ramamoorthy
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
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19
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Holton NW, Singhal M, Kumar A, Ticho AL, Manzella CR, Malhotra P, Jarava D, Saksena S, Dudeja PK, Alrefai WA, Gill RK. Hepatocyte nuclear factor-4α regulates expression of the serotonin transporter in intestinal epithelial cells. Am J Physiol Cell Physiol 2020; 318:C1294-C1304. [PMID: 32348179 PMCID: PMC7311735 DOI: 10.1152/ajpcell.00477.2019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 04/23/2020] [Accepted: 04/23/2020] [Indexed: 12/20/2022]
Abstract
The serotonin transporter (SERT) functions to regulate the availability of serotonin (5-HT) in the brain and intestine. An intestine-specific mRNA variant arising from a unique transcription start site and alternative promoter in the SERT gene has been identified (iSERT; spanning exon 1C). A decrease in SERT is implicated in several gut disorders, including inflammatory bowel diseases (IBD). However, little is known about mechanisms regulating the iSERT variant, and a clearer understanding is warranted for targeting SERT for the treatment of gut disorders. The current studies examined the expression of iSERT across different human intestinal regions and investigated its regulation by HNF4α (hepatic nuclear factor-4α), a transcription factor important for diverse cellular functions. iSERT mRNA abundance was highest in the human ileum and Caco-2 cell line. iSERT mRNA expression was downregulated by loss of HNF4α (but not HNF1α, HNF1β, or FOXA1) in Caco-2 cells. Overexpression of HNF4α increased iSERT mRNA concomitant with an increase in SERT protein. Progressive promoter deletion and site-directed mutagenesis revealed that the HNF4α response element spans nucleotides -1,163 to -1150 relative to the translation start site. SERT mRNA levels in the intestine were drastically reduced in the intestine-specific HNF4α-knockout mice relative to HNF4αFL/FL mice. Both HNF4α and SERT mRNA levels were also downregulated in mouse model of ileitis (SAMP) compared with AKR control mice. These results establish the transcriptional regulation of iSERT at the gut-specific internal promoter (hSERTp2) and have identified HNF4α as a critical modulator of basal SERT expression in the intestine.
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Affiliation(s)
- Nathaniel W Holton
- Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, Illinois
| | - Megha Singhal
- Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, Illinois
| | - Anoop Kumar
- Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, Illinois
| | - Alexander L Ticho
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois
| | - Christopher R Manzella
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois
| | - Pooja Malhotra
- Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, Illinois
| | - David Jarava
- Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, Illinois
| | - Seema Saksena
- Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, Illinois
- Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Pradeep K Dudeja
- Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, Illinois
- Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Waddah A Alrefai
- Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, Illinois
- Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Ravinder K Gill
- Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, Illinois
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20
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Effects of stress on functional connectivity during problem solving. Neuroimage 2020; 208:116407. [DOI: 10.1016/j.neuroimage.2019.116407] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 10/24/2019] [Accepted: 11/26/2019] [Indexed: 11/20/2022] Open
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21
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Annamalai B, Ragu Varman D, Horton RE, Daws LC, Jayanthi LD, Ramamoorthy S. Histamine Receptors Regulate the Activity, Surface Expression, and Phosphorylation of Serotonin Transporters. ACS Chem Neurosci 2020; 11:466-476. [PMID: 31916747 DOI: 10.1021/acschemneuro.9b00664] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Reuptake and clearance of released serotonin (5-HT) are critical in serotonergic neurotransmission. Serotonin transporter (SERT) is mainly responsible for clearing the extracellular 5-HT. Controlled trafficking, phosphorylation, and protein stability have been attributed to robust SERT activity. H3 histamine receptors (H3Rs) act in conjunction and regulate 5-HT release. H3Rs are expressed in the nervous system and located at the serotonergic terminals, where they act as heteroreceptors. Although histaminergic and serotonergic neurotransmissions are thought to be two separate events, whether H3Rs influence SERT in the CNS to control 5-HT reuptake has never been addressed. With a priori knowledge gained from our studies, we explored the possibility of using rat hippocampal synaptosomal preparations. We found that treatment with H3R/H4R-agonists immepip and (R)-(-)-α-methyl-histamine indeed resulted in a time- and concentration-dependent decrease in 5-HT transport. On the other hand, treatment with H3R/H4R-inverse agonist thioperamide caused a moderate increase in 5-HT uptake while blocking the inhibitory effect of H3R/H4R agonists. When investigated further, immepip treatment reduced the level of SERT on the plasma membrane and its phosphorylation. Likewise, CaMKII inhibitor KN93 or calcineurin inhibitor cyclosporine A also inhibited SERT function; however, an additive effect with immepip was not seen. High-speed in vivo chronoamperometry demonstrated that immepip delayed 5-HT clearance while thioperamide accelerated 5-HT clearance from the extracellular space. Immepip selectively inhibited SERT activity in the hippocampus and cortex but not in the striatum, midbrain, and brain stem. Thus, we report here a novel mechanism of regulating SERT activity by H3R-mediated CaMKII/calcineurin pathway in a brain-region-specific manner and perhaps synaptic 5-HT in the CNS that controls 5-HT clearance.
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Affiliation(s)
- Balasubramaniam Annamalai
- Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, United States
| | - Durairaj Ragu Varman
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298, United States
| | - Rebecca E. Horton
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States
| | - Lynette C. Daws
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States
| | - Lankupalle D. Jayanthi
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298, United States
| | - Sammanda Ramamoorthy
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298, United States
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Del Colle A, Israelyan N, Gross Margolis K. Novel aspects of enteric serotonergic signaling in health and brain-gut disease. Am J Physiol Gastrointest Liver Physiol 2020; 318:G130-G143. [PMID: 31682158 PMCID: PMC6985840 DOI: 10.1152/ajpgi.00173.2019] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 10/17/2019] [Accepted: 10/17/2019] [Indexed: 02/08/2023]
Abstract
Gastrointestinal (GI) comorbidities are common in individuals with mood and behavioral dysfunction. Similarly, patients with GI problems more commonly suffer from co-morbid psychiatric diagnoses. Although the central and enteric nervous systems (CNS and ENS, respectively) have largely been studied separately, there is emerging interest in factors that may contribute to disease states involving both systems. There is strong evidence to suggest that serotonin may be an important contributor to these brain-gut conditions. Serotonin has long been recognized for its critical functions in CNS development and function. The majority of the body's serotonin, however, is produced in the GI tract, where it plays key roles in ENS development and function. Further understanding of the specific impact that enteric serotonin has on brain-gut disease may lay the foundation for the creation of novel therapeutic targets. This review summarizes the current data focusing on the important roles that serotonin plays in ENS development and motility, with a focus on novel aspects of serotonergic signaling in medical conditions in which CNS and ENS co-morbidities are common, including autism spectrum disorders and depression.
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Affiliation(s)
- Andrew Del Colle
- Morgan Stanley Children's Hospital, Department of Pediatrics, Columbia University Medical Center, New York, New York
| | - Narek Israelyan
- Morgan Stanley Children's Hospital, Department of Pediatrics, Columbia University Medical Center, New York, New York
- Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, New York
| | - Kara Gross Margolis
- Morgan Stanley Children's Hospital, Department of Pediatrics, Columbia University Medical Center, New York, New York
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23
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Zhang E, Liao P. Brain‐derived neurotrophic factor and post‐stroke depression. J Neurosci Res 2019; 98:537-548. [DOI: 10.1002/jnr.24510] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 07/21/2019] [Accepted: 07/22/2019] [Indexed: 12/16/2022]
Affiliation(s)
- Eric Zhang
- Western University of Health Sciences Pomona CA
| | - Ping Liao
- Calcium Signalling Laboratory National Neuroscience Institute Singapore
- Duke‐NUS Medical School Singapore
- Health and Social Sciences Singapore Institute of Technology Singapore
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Murthi P, Vaillancourt C. RETRACTED: Placental serotonin systems in pregnancy metabolic complications associated with maternal obesity and gestational diabetes mellitus. Biochim Biophys Acta Mol Basis Dis 2019; 1866:165391. [PMID: 30738809 DOI: 10.1016/j.bbadis.2019.01.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 01/08/2019] [Accepted: 01/10/2019] [Indexed: 12/12/2022]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).
The publication was retracted by request of the authors following an investigation by Monash University performed following its Procedures for Investigating Code Breaches and in accordance with the Australian Code for the Responsible Conduct of Research.
The University concluded on the balance of probability that a significant part of the text in the paper was included without knowledge, without consent and without correct attribution of the original author who, at the time, was a student at the University. The results discussed in the review article are still scientifically valid.
☆
This article is part of a Special Issue entitled: Membrane Transporters and Receptors in Pregnancy Metabolic Complications edited by Luis Sobrevia.
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Affiliation(s)
- Padma Murthi
- Department of Medicine, School of Clinical Sciences, Department of Physiology, Monash University, Clayton, Victoria, Australia; Hudson Institute of Medical Research, The Ritchie Centre, Clayton, Victoria, Australia; Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, Victoria, Australia.
| | - Cathy Vaillancourt
- INRS-Institut Armand-Frappier, Université du Québec and Biomed Research Center, 531 Boulevard des Prairies, Laval, QC H7V 1B7, Canada; Center for Interdisciplinary Research on Well-Being, Health, Society and Environment, Université du Québec à Montréal, Montréal, QC H3C 3P8, Canada
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25
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Jiménez-Treviño L, Saiz PA, García-Portilla MP, Blasco-Fontecilla H, Carli V, Iosue M, Jaussent I, López-Castroman J, Vaquero-Lorenzo C, Sarchiapone M, Baca-García E, Courtet P, Bobes J. 5-HTTLPR-brain-derived neurotrophic factor (BDNF) gene interactions and early adverse life events effect on impulsivity in suicide attempters. World J Biol Psychiatry 2019; 20:137-149. [PMID: 28914102 DOI: 10.1080/15622975.2017.1376112] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
OBJECTIVES An expanding body of research suggests that childhood adverse experiences can lead to different negative health outcomes, including attempted suicide. Serotonergic genes such as the promoter region of the serotonin transporter gene (5-HTTLPR) have been associated both with impulsivity in suicide attempts and reactivity to environmental stress exposure. BDNF gene may play an epigenetic role. METHODS We studied the influence of childhood stressful events and 5-HTTLPR genotype on impulsivity measured by Barratt Impulsivity Scale (BIS-10) in a multicentre sample of 1,655 suicide attempters (69.4% women, 30.6% men; mean age 40.13 years). A co-dominant additive genetic model was used for the statistical analyses. Interaction between 5-HTTLPR genotype and early trauma exposure was tested using moderated and multiple regression techniques. Interaction plots were used to explore BDNF genotype modulation. RESULTS Mildly higher impulsivity scores were found in men with SS compared with SL or LL genotypes, and men with childhood emotional and physical abuse. Interaction analyses showed that combination of 5-HTTLPR-SS genotype and early trauma exposure increase impulsivity scores independently. Impulsivity scores were not affected by the modulation of BDNF genes. CONCLUSIONS Childhood trauma and 5-HTTLPR genotype seem to be independently involved in suicide attempts, sharing a common pathway of increasing impulsivity.
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Affiliation(s)
- Luis Jiménez-Treviño
- a Department of Psychiatry , School of Medicine, University of Oviedo, Centro de Investigacion Biomedica en Red de Salud Mental - CIBERSAM, Instituto de Neurociencias del Principado de Asturias, INEUROPA , Oviedo , Spain
| | - Pilar Alejandra Saiz
- a Department of Psychiatry , School of Medicine, University of Oviedo, Centro de Investigacion Biomedica en Red de Salud Mental - CIBERSAM, Instituto de Neurociencias del Principado de Asturias, INEUROPA , Oviedo , Spain
| | - Maria Paz García-Portilla
- a Department of Psychiatry , School of Medicine, University of Oviedo, Centro de Investigacion Biomedica en Red de Salud Mental - CIBERSAM, Instituto de Neurociencias del Principado de Asturias, INEUROPA , Oviedo , Spain
| | - Hilario Blasco-Fontecilla
- b Department of Psychiatry , Jimenez Diaz Foundation, Universidad Autonoma de Madrid, CIBERSAM , Madrid , Spain
| | - Vladimir Carli
- c National Centre for Suicide Research and Prevention of Mental Ill-Health (NASP) , Karolinska Institute , Stockholm , Sweden
| | - Miriam Iosue
- d Department of Medicine and Health Sciences , University of Molise, Via Francesco De Sanctis , Campobasso , Italy
| | | | | | | | - Marco Sarchiapone
- d Department of Medicine and Health Sciences , University of Molise, Via Francesco De Sanctis , Campobasso , Italy.,g National Institute for Health, Migration and Poverty , Rome , Italy
| | - Enrique Baca-García
- b Department of Psychiatry , Jimenez Diaz Foundation, Universidad Autonoma de Madrid, CIBERSAM , Madrid , Spain
| | - Philippe Courtet
- h Department of Psychological Medicine and Psychiatry , University of Montpellier I, Lapeyronie Hospital, INSERM E99 30 , Montpellier , France
| | - Julio Bobes
- a Department of Psychiatry , School of Medicine, University of Oviedo, Centro de Investigacion Biomedica en Red de Salud Mental - CIBERSAM, Instituto de Neurociencias del Principado de Asturias, INEUROPA , Oviedo , Spain
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Blakely RD, El Mestikawy S, Robinson MB. The brain in flux: Genetic, physiologic, and therapeutic perspectives on transporters in the CNS. Neurochem Int 2018; 123:1-6. [PMID: 30571999 DOI: 10.1016/j.neuint.2018.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The brain has specific properties that make it uniquely dependent upon transporters. This is the 3rd edition of a biennial special issue that originates from a scientific meeting devoted to studies of transporters and their relationship to brain function and to neurodevelopmental, neurologic, and psychiatric disorders. The field continues to rapidly evolve with advances in studies of structure that inform mechanism, with genetic analyses in humans revealing surprising aspects of biology, and with integrated cellular to whole animal analyses of the role of transporters in their control of physiology and pathophysiology. This special issue includes a sampling of review articles that address timely questions of the field followed by several primary research articles.
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Affiliation(s)
- Randy D Blakely
- Florida Atlantic University Brain Institute, Department of Biomedical Science, Florida Atlantic University, Jupiter, FL, 33458, United States
| | - Salah El Mestikawy
- Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, QC, H4H 1R3, Canada; Sorbonne Universités, Université Pierre et Marie Curie UM 119 - CNRS UMR 8246 - INSERM U1130, Neurosciences Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), 75005, Paris, France
| | - Michael B Robinson
- Departments of Pediatrics and Systems Pharmacology and Translational Therapeutics, Children's Hospital of Philadelphia/University of Pennsylvania, Philadelphia, PA, 19104, United States.
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Tolahunase MR, Sagar R, Dada R. 5-HTTLPR and MTHFR 677C>T polymorphisms and response to yoga-based lifestyle intervention in major depressive disorder: A randomized active-controlled trial. Indian J Psychiatry 2018; 60:410-426. [PMID: 30581206 PMCID: PMC6278208 DOI: 10.4103/psychiatry.indianjpsychiatry_398_17] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND There is growing evidence suggesting that both genetic and environmental factors modulate treatment outcome in, a highly heterogeneous, major depressive disorder (MDD). 5-HTTLPR variant of the serotonin transporter gene (SLC6A4) and MTHFR 677C>T polymorphisms have been linked to the pathogenesis of MDD, and antidepressant treatment response. The evidence is lacking on the clinical utility of yoga in patients with MDD who have 5-HTTLPR and MTHFR 677C>T polymorphisms and less likely to respond to medications (SSRIs). AIMS We aimed to examine the impact of YBLI in those who have susceptible 5-HTTLPR and MTHFR 677C>T polymorphisms and are less likely to drug therapy with SSRIs. SETTINGS AND DESIGN In a 12 week randomized active-controlled trial, MDD patients (n = 178) were randomized to receive YBLI or drug therapy. METHODS Genotyping was conducted using PCR-based methods. The clinical remission was defined as BDI-II score ≤ 9. STATISTICAL ANALYSIS USED An intent-to-treat analysis was performed, and the association of genotype with treatment remission consisted of the logistic regression model. A P value of <0.05 was considered statistically significant. RESULTS Multivariate logistic regression models for remission including either 5-HTTLPR or MTHFR 677C>T genotypes showed statistically significant odds of remission in YOGA arm vs. DRUG arm. Neither 5-HTTLPR nor MTHFR 677C>T genotype showed any influence on remission to YBLI (P = 0.73 and P = 0.64, respectively). Further analysis showed childhood adversity interact with 5-HTTLPR and MTHFR 677C>T polymorphisms to decrease treatment response in DRUG treatment arm, but not in YOGA arm. CONCLUSIONS YBLI provides MDD remission in those who have susceptible 5-HTTLPR and MTHFR 677C>T polymorphisms and are resistant to SSRIs treatment. YBLI may be therapeutic for MDD independent of heterogeneity in its etiopathogenesis.
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Affiliation(s)
- Madhuri R Tolahunase
- Department of Anatomy, Lab for Molecular Reproduction and Genetics, All India Institute of Medical Sciences, New Delhi, India
| | - Rajesh Sagar
- Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India
| | - Rima Dada
- Department of Anatomy, Lab for Molecular Reproduction and Genetics, All India Institute of Medical Sciences, New Delhi, India
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Niitsu K, Rice MJ, Houfek JF, Stoltenberg SF, Kupzyk KA, Barron CR. A Systematic Review of Genetic Influence on Psychological Resilience. Biol Res Nurs 2018; 21:61-71. [DOI: 10.1177/1099800418800396] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
When exposed to adversity, some individuals are at an increased risk of posttraumatic stress disorder, experiencing persistent biopsychosocial disturbances, whereas others adapt well, described as resilience. Resilience is a complex biopsychosocial phenomenon conceptualized as adaptation to adversity influenced by an individual’s genetic variants, epistasis, epigenetics, and gene-by-environment interactions. Studies on psychological resilience have focused on behavioral and psychosocial variables with far less examination of the genetic contributions. The purpose of this review is to identify specific genetic variants contributing to the biological capacity for psychological resilience. PubMed and PsycINFO were searched using the following key words: psychological resilience AND genotype(s). Additional articles were identified from the Human Genome Epidemiology Navigator using the term resilience, psychological. Ten studies met the criteria. Six genes were empirically associated with psychological resilience: serotonin-transporter-linked polymorphic region ( 5-HTTLPR), dopamine receptor D4, brain-derived neurotrophic factor ( BDNF), corticotropin-releasing hormone receptor 1, oxytocin receptor and regulator of G-protein signaling 2 . The findings of this systematic review suggest that the L/L or L’/L’ genotype of 5-HTTLPR and rs25531 in children/adolescents and the S/S or S’/S’ genotype in adults are most frequently related to resilience. Additionally, the Val/Val genotype of rs6265 in BDNF in Caucasians was also associated with resilience. There are numerous factors contributing to the complexity of determining the genetic influence on resilience including analysis of rs25531, assumptions of the mode of inheritance, operationalization of resilience, demographic and population characteristics, sample size, and other types of genetic influence including epistasis and epigenetics. While current evidence is supportive, further investigation of the genetic influence on resilience is required.
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Affiliation(s)
- Kosuke Niitsu
- College of Nursing, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Michael J. Rice
- College of Nursing, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Julia F. Houfek
- College of Nursing, University of Nebraska Medical Center, Omaha, NE, USA
| | | | - Kevin A. Kupzyk
- College of Nursing, University of Nebraska Medical Center, Omaha, NE, USA
| | - Cecilia R. Barron
- College of Nursing, University of Nebraska Medical Center, Omaha, NE, USA
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Gonda X, Petschner P, Eszlari N, Baksa D, Edes A, Antal P, Juhasz G, Bagdy G. Genetic variants in major depressive disorder: From pathophysiology to therapy. Pharmacol Ther 2018; 194:22-43. [PMID: 30189291 DOI: 10.1016/j.pharmthera.2018.09.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In spite of promising preclinical results there is a decreasing number of new registered medications in major depression. The main reason behind this fact is the lack of confirmation in clinical studies for the assumed, and in animals confirmed, therapeutic results. This suggests low predictive value of animal studies for central nervous system disorders. One solution for identifying new possible targets is the application of genetics and genomics, which may pinpoint new targets based on the effect of genetic variants in humans. The present review summarizes such research focusing on depression and its therapy. The inconsistency between most genetic studies in depression suggests, first of all, a significant role of environmental stress. Furthermore, effect of individual genes and polymorphisms is weak, therefore gene x gene interactions or complete biochemical pathways should be analyzed. Even genes encoding target proteins of currently used antidepressants remain non-significant in genome-wide case control investigations suggesting no main effect in depression, but rather an interaction with stress. The few significant genes in GWASs are related to neurogenesis, neuronal synapse, cell contact and DNA transcription and as being nonspecific for depression are difficult to harvest pharmacologically. Most candidate genes in replicable gene x environment interactions, on the other hand, are connected to the regulation of stress and the HPA axis and thus could serve as drug targets for depression subgroups characterized by stress-sensitivity and anxiety while other risk polymorphisms such as those related to prominent cognitive symptoms in depression may help to identify additional subgroups and their distinct treatment. Until these new targets find their way into therapy, the optimization of current medications can be approached by pharmacogenomics, where metabolizing enzyme polymorphisms remain prominent determinants of therapeutic success.
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Affiliation(s)
- Xenia Gonda
- Department of Psychiatry and Psychotherapy, Kutvolgyi Clinical Centre, Semmelweis University, Budapest, Hungary; NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary; MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
| | - Peter Petschner
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary; Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
| | - Nora Eszlari
- NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary; Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
| | - Daniel Baksa
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary; SE-NAP 2 Genetic Brain Imaging Migraine Research Group, Hungarian Academy of Sciences, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary
| | - Andrea Edes
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary; SE-NAP 2 Genetic Brain Imaging Migraine Research Group, Hungarian Academy of Sciences, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary
| | - Peter Antal
- Department of Measurement and Information Systems, Budapest University of Technology and Economics, Budapest, Hungary
| | - Gabriella Juhasz
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary; SE-NAP 2 Genetic Brain Imaging Migraine Research Group, Hungarian Academy of Sciences, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary; Neuroscience and Psychiatry Unit, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK
| | - Gyorgy Bagdy
- NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary; MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary; Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary.
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Nyarko JNK, Quartey MO, Heistad RM, Pennington PR, Poon LJ, Knudsen KJ, Allonby O, El Zawily AM, Freywald A, Rauw G, Baker GB, Mousseau DD. Glycosylation States of Pre- and Post-synaptic Markers of 5-HT Neurons Differ With Sex and 5-HTTLPR Genotype in Cortical Autopsy Samples. Front Neurosci 2018; 12:545. [PMID: 30147642 PMCID: PMC6096231 DOI: 10.3389/fnins.2018.00545] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 07/19/2018] [Indexed: 11/13/2022] Open
Abstract
The serotonin (5-hydroxytryptamine, 5-HT) transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) is thought to alter 5-HT signaling and contribute to behavioral and cognitive phenotypes in depression as well as Alzheimer disease (AD). We explored how well the short (S) and long (L) alleles of the 5-HTTLPR align with serotoninergic indices in 60 autopsied cortical samples from early-onset AD/EOAD and late-onset AD/LOAD donors, and age- and sex-matched controls. Stratifying data by either diagnosis-by-genotype or by sex-by-genotype revealed that the donor's 5-HTTLPR genotype, i.e., L/L, S/L, or S/S, did not affect 5-HTT mRNA or protein expression. However, the glycosylation of 5-HTT was significantly higher in control female (vs. male) samples and tended to decrease in female EOAD/LOAD samples, but remained unaltered in male LOAD samples. Glycosylated forms of the vesicular monoamine transporter (VMAT2) were lower in both male and female AD samples, while a sex-by-genotype stratification revealed a loss of VMAT2 glycosylation specifically in females with an L/L genotype. VMAT2 and 5-HTT glycosylation were correlated in male samples and inversely correlated in female samples in both stratification models. The S/S genotype aligned with lower levels of 5-HT turnover in females (but not males) and with an increased glycosylation of the post-synaptic 5-HT2C receptor. Interestingly, the changes in presynaptic glycosylation were evident primarily in female carriers of the APOE ε4 risk factor for AD. Our data do not support an association between 5-HTTLPR genotype and 5-HTT expression, but they do reveal a non-canonical association of 5-HTTLPR genotype with sex-dependent glycosylation changes in pre- and post-synaptic markers of serotoninergic neurons. These patterns of change suggest adaptive responses in 5-HT signaling and could certainly be contributing to the female prevalence in risk for either depression or AD.
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Affiliation(s)
- Jennifer N K Nyarko
- Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, Saskatoon, SK, Canada
| | - Maa O Quartey
- Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, Saskatoon, SK, Canada
| | - Ryan M Heistad
- Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, Saskatoon, SK, Canada
| | - Paul R Pennington
- Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, Saskatoon, SK, Canada
| | - Lisa J Poon
- Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, Saskatoon, SK, Canada
| | - Kaeli J Knudsen
- Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, Saskatoon, SK, Canada
| | - Odette Allonby
- Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, Saskatoon, SK, Canada
| | - Amr M El Zawily
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Andrew Freywald
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Gail Rauw
- Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
| | - Glen B Baker
- Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
| | - Darrell D Mousseau
- Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, Saskatoon, SK, Canada
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Kitzlerová E, Fišar Z, Lelková P, Jirák R, Zvěřová M, Hroudová J, Manukyan A, Martásek P, Raboch J. Interactions Among Polymorphisms of Susceptibility Loci for Alzheimer's Disease or Depressive Disorder. Med Sci Monit 2018; 24:2599-2619. [PMID: 29703883 PMCID: PMC5944403 DOI: 10.12659/msm.907202] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background Several genetic susceptibility loci for major depressive disorder (MDD) or Alzheimer’s disease (AD) have been described. Interactions among polymorphisms are thought to explain the differences between low- and high-risk groups. We tested for the contribution of interactions between multiple functional polymorphisms in the risk of MDD or AD. Material/Methods A genetic association case-control study was performed in 68 MDD cases, 84 AD cases (35 of them with comorbid depression), and 90 controls. The contribution of 7 polymorphisms from 5 genes (APOE, HSPA1A, SLC6A4, HTR2A, and BDNF) related to risk of MDD or AD development was analyzed. Results Significant associations were found between MDD and interactions among polymorphisms in HSPA1A, SLC6A4, and BDNF or HSPA1A, BDNF, and APOE genes. For polymorphisms in the APOE gene in AD, significant differences were confirmed on the distributions of alleles and genotype rates compared to the control or MDD. Increased probability of comorbid depression was found in patients with AD who do not carry the ɛ4 allele of APOE. Conclusions Assessment of the interactions among polymorphisms of susceptibility loci in both MDD and AD confirmed a synergistic effect of genetic factors influencing inflammatory, serotonergic, and neurotrophic pathways at these heterogenous complex diseases. The effect of interactions was greater in MDD than in AD. A presence of the ɛ4 allele was confirmed as a genetic susceptibility factor in AD. Our findings indicate a role of APOE genotype in onset of comorbid depression in a subgroup of patients with AD who are not carriers of the APOE ɛ4 allele.
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Affiliation(s)
- Eva Kitzlerová
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Zdeněk Fišar
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Petra Lelková
- Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Roman Jirák
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Martina Zvěřová
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Jana Hroudová
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Ada Manukyan
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Pavel Martásek
- Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Jiří Raboch
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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Serotonergic psychedelics and personality: A systematic review of contemporary research. Neurosci Biobehav Rev 2018; 87:118-132. [DOI: 10.1016/j.neubiorev.2018.02.004] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 01/12/2018] [Accepted: 02/07/2018] [Indexed: 01/17/2023]
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Yamazaki K, Yoshino Y, Mori T, Okita M, Yoshida T, Mori Y, Ozaki Y, Sao T, Iga JI, Ueno SI. Association Study and Meta-Analysis of Polymorphisms, Methylation Profiles, and Peripheral mRNA Expression of the Serotonin Transporter Gene in Patients with Alzheimer's Disease. Dement Geriatr Cogn Disord 2018; 41:334-47. [PMID: 27414430 DOI: 10.1159/000447324] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/01/2016] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIM The aim of this study was to elucidate the relationship between Alzheimer's disease (AD) and the serotonin transporter gene (SLC6A4). METHODS AD subjects (n = 43) and controls (n = 47) were recruited and evaluated. In leukocytes, we evaluated two polymorphisms in SLC6A4, the serotonin transporter length polymorphic region (5-HTT-LPR) and rs25531, as well as methylation rates of the SLC6A4 promoter region and the SLC6A4 mRNA expression level. We also performed a meta-analysis to examine the relationship between the frequency of the L allele and the risk of AD. RESULTS The distributions of 5-HTT-LPR and rs25531 polymorphisms in AD subjects were not different from those of controls. Although the methylation rates in AD subjects were not significantly different from those of controls, the expression level in AD subjects was significantly higher than in controls. Additionally, the expression level in AD subjects was significantly correlated with apathy. Meta-analysis revealed that the L/L genotype significantly reduced the risk of AD, but only in the Caucasian population. CONCLUSION Higher SLC6A4 mRNA expression in leukocytes in AD was associated with apathy regardless of SLC6A4 genotypes and methylation rates of the promoter region. The L/L genotype may reduce the risk of AD in the Caucasian population.
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Affiliation(s)
- Kiyohiro Yamazaki
- Department of Neuropsychiatry, Molecules and Function, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Japan
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Mueller JC, Edelaar P, Baños-Villalba A, Carrete M, Potti J, Blas J, Tella JL, Kempenaers B. Selection on a behaviour-related gene during the first stages of the biological invasion pathway. Mol Ecol 2017; 26:6110-6121. [PMID: 28926158 DOI: 10.1111/mec.14353] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 08/30/2017] [Accepted: 09/05/2017] [Indexed: 01/22/2023]
Abstract
Human-induced biological invasions are common worldwide and often have negative impacts on wildlife and human societies. Several studies have shown evidence for selection on invaders after introduction to the new range. However, selective processes already acting prior to introduction have been largely neglected. Here, we tested whether such early selection acts on known behaviour-related gene variants in the yellow-crowned bishop (Euplectes afer), a pet-traded African songbird. We tested for nonrandom allele frequency changes after trapping, acclimation and survival in captivity. We also compared the native source population with two independent invasive populations. Allele frequencies of two SNPs in the dopamine receptor D4 (DRD4) gene-known to be linked to behavioural activity in response to novelty in this species-significantly changed over all early invasion stages. They also differed between the African native population and the two invading European populations. The two-locus genotype associated with reduced activity declined consistently, but strongest at the trapping stage. Overall genetic diversity did not substantially decrease, and there is little evidence for new alleles in the introduced populations, indicating that selection at the DRD4 gene predominantly worked on the standing genetic variation already present in the native population. Our study demonstrates selection on a behaviour-related gene during the first stages of a biological invasion. Thus, pre-establishment stages of a biological invasion do not only determine the number of propagules that are introduced (their quantity), but also their phenotypic and genetic characteristics (their quality).
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Affiliation(s)
- Jakob C Mueller
- Department of Behavioural Ecology & Evolutionary Genetics, Max Planck Institute for Ornithology, Seewiesen, Germany
| | - Pim Edelaar
- Department of Molecular Biology and Biochemical Engineering, University Pablo de Olavide, Sevilla, Spain
| | - Adrián Baños-Villalba
- Department of Molecular Biology and Biochemical Engineering, University Pablo de Olavide, Sevilla, Spain
| | - Martina Carrete
- Department of Conservation Biology, Estación Biológica de Doñana - CSIC, Sevilla, Spain.,Department of Physical, Chemical and Natural Systems, University Pablo de Olavide, Sevilla, Spain
| | - Jaime Potti
- Department of Evolutionary Ecology, Estación Biológica de Doñana - CSIC, Sevilla, Spain
| | - Julio Blas
- Department of Conservation Biology, Estación Biológica de Doñana - CSIC, Sevilla, Spain
| | - Jose Luis Tella
- Department of Conservation Biology, Estación Biológica de Doñana - CSIC, Sevilla, Spain
| | - Bart Kempenaers
- Department of Behavioural Ecology & Evolutionary Genetics, Max Planck Institute for Ornithology, Seewiesen, Germany
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Abstract
We tested the hypothesis that gestational diabetes mellitus (GDM) alters the DNA methylation pattern of the fetal serotonin transporter gene (SLC6A4), and examined the functional relevance of DNA methylation for regulation of the SLC6A4 expression in the human placenta. The study included 50 mother-infant pairs. Eighteen mothers were diagnosed with GDM and 32 had normal glucose tolerance (NGT). All neonates were of normal birth weight and born at term by planned Cesarean section. DNA and RNA were isolated from samples of tissue collected from the fetal side of the placenta immediately after delivery. DNA methylation was quantified at 7 CpG sites within the SLC6A4 distal promoter region using PCR amplification of bisulfite treated DNA and subsequent DNA sequencing. SLC6A4 mRNA levels were measured by reverse transcription—quantitative PCR (RT-qPCR). Functional SLC6A4 polymorphisms (5HTTLPR, STin2, rs25531) were genotyped using standard PCR-based procedures. Average DNA methylation across the 7 analyzed loci was decreased in the GDM as compared to the NGT group (by 27.1%, p = 0.037) and negatively correlated, before and after adjustment for potential confounder/s, with maternal plasma glucose levels at the 24th to 28th week of gestation (p<0.05). Placental SLC6A4 mRNA levels were inversely correlated with average DNA methylation (p = 0.010) while no statistically significant association was found with the SLC6A4 genotypes (p>0.05). The results suggest that DNA methylation of the fetal SLC6A4 gene is sensitive to the maternal metabolic state in pregnancy. They also indicate a predominant role of epigenetic over genetic mechanisms in the regulation of SLC6A4 expression in the human placenta. Longitudinal studies in larger cohorts are needed to verify these results and determine to which degree placental SLC6A4 changes may contribute to long-term outcomes of infants exposed to GDM.
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Sinopoli VM, Burton CL, Kronenberg S, Arnold PD. A review of the role of serotonin system genes in obsessive-compulsive disorder. Neurosci Biobehav Rev 2017; 80:372-381. [PMID: 28576508 DOI: 10.1016/j.neubiorev.2017.05.029] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 04/20/2017] [Accepted: 05/29/2017] [Indexed: 12/16/2022]
Abstract
Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder that causes the patient to experience intrusive thoughts and/or to carry out repetitive, ritualized behaviors that are time consuming and impairing. OCD is familial and heritable. The genetic factors responsible for pathogenesis, however, remain largely unknown despite the numerous candidate gene studies conducted. Based on efficacy of serotonin reuptake inhibitors (SRIs) in treating OCD, serotonin system genes have been a dominant focus in OCD candidate gene studies. We review the most commonly studied candidate serotonin system gene variants (specifically in SLC6A4, HTR2A, HTR1B, and HTR2C) and their association with OCD. Although findings to date are mixed, serotonin transporter polymorphism 5-HTTLPR and HTR2A polymorphism rs6311 (or rs6313) are most consistently associated with OCD. Mixed findings may be the result of genetic complexity and phenotypic heterogeneity that future studies should account for. Homogenous patient subgroups reflecting OCD symptom dimensions, OCD subtypes, and sex should be used for gene discovery.
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Affiliation(s)
- Vanessa M Sinopoli
- Institute of Medical Science, University of Toronto, Canada; Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Canada
| | - Christie L Burton
- Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Canada; Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada
| | - Sefi Kronenberg
- Department of Psychiatry, The Hospital for Sick Children, Toronto, Canada; Department of Psychiatry, University of Toronto, Canada
| | - Paul D Arnold
- Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Canada; Mathison Centre for Mental Health Research & Education, Hotchkiss Brain Institute, University of Calgary, Canada; Departments of Psychiatry and Medical Genetics, Cumming School of Medicine, University of Calgary, Canada.
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Iurescia S, Seripa D, Rinaldi M. Looking Beyond the 5-HTTLPR Polymorphism: Genetic and Epigenetic Layers of Regulation Affecting the Serotonin Transporter Gene Expression. Mol Neurobiol 2016; 54:8386-8403. [DOI: 10.1007/s12035-016-0304-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 11/16/2016] [Indexed: 01/01/2023]
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Pharmacogenetics and Imaging-Pharmacogenetics of Antidepressant Response: Towards Translational Strategies. CNS Drugs 2016; 30:1169-1189. [PMID: 27752945 DOI: 10.1007/s40263-016-0385-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Genetic variation underlies both the response to antidepressant treatment and the occurrence of side effects. Over the past two decades, a number of pharmacogenetic variants, among these the SCL6A4, BDNF, FKBP5, GNB3, GRIK4, and ABCB1 genes, have come to the forefront in this regard. However, small effects sizes, mixed results in independent samples, and conflicting meta-analyses results led to inherent difficulties in the field of pharmacogenetics translating these findings into clinical practice. Nearly all antidepressant pharmacogenetic variants have potentially pleiotropic effects in which they are associated with major depressive disorder, intermediate phenotypes involved in emotional processes, and brain areas affected by antidepressant treatment. The purpose of this article is to provide a comprehensive review of the advances made in the field of pharmacogenetics of antidepressant efficacy and side effects, imaging findings of antidepressant response, and the latest results in the expanding field of imaging-pharmacogenetics studies. We suggest there is mounting evidence that genetic factors exert their impact on treatment response by influencing brain structural and functional changes during antidepressant treatment, and combining neuroimaging and genetic methods may be a more powerful way to detect biological mechanisms of response than either method alone. The most promising imaging-pharmacogenetics findings exist for the SCL6A4 gene, with converging associations with antidepressant response, frontolimbic predictors of affective symptoms, and normalization of frontolimbic activity following antidepressant treatment. More research is required before imaging-pharmacogenetics informed personalized medicine can be applied to antidepressant treatment; nevertheless, inroads have been made towards assessing genetic and neuroanatomical liability and potential clinical application.
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An integrative review of methylation at the serotonin transporter gene and its dialogue with environmental risk factors, psychopathology and 5-HTTLPR. Neurosci Biobehav Rev 2016; 72:190-209. [PMID: 27880876 DOI: 10.1016/j.neubiorev.2016.11.011] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 11/04/2016] [Accepted: 11/06/2016] [Indexed: 11/24/2022]
Abstract
Gene-environment (G×E) interactions have largely been regarded as the root of many complex disorders, including several psychiatric disorders. In this regard, it has been hypothesized that epigenetic mechanisms may be the main mediators of such interactions. Of particular interest is the previously described interaction between psychosocial stress and genetic variability of the serotonin transporter gene (SLC6A4) in its polymorphic region 5-HTTLPR. Here we review the literature concerning SLC6A4 methylation in association with environmental, clinical or genetic variables. While SLC6A4 hypermethylation has typically been described to be independently associated with both early life stress and depressive disorders, only a few papers address whether methylation could mediate the interaction between stress and 5-HTTLPR in predicting psychopathological risk. Nevertheless, research preliminarily indicates a methylation-driven increased vulnerability of carriers of the short allele of 5-HTTLPR to psychiatric disorders when exposed to early stress or soon after exposure to stress.
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Bermingham DP, Blakely RD. Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters. Pharmacol Rev 2016; 68:888-953. [PMID: 27591044 PMCID: PMC5050440 DOI: 10.1124/pr.115.012260] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Modulation of neurotransmission by the monoamines dopamine (DA), norepinephrine (NE), and serotonin (5-HT) is critical for normal nervous system function. Precise temporal and spatial control of this signaling in mediated in large part by the actions of monoamine transporters (DAT, NET, and SERT, respectively). These transporters act to recapture their respective neurotransmitters after release, and disruption of clearance and reuptake has significant effects on physiology and behavior and has been linked to a number of neuropsychiatric disorders. To ensure adequate and dynamic control of these transporters, multiple modes of control have evolved to regulate their activity and trafficking. Central to many of these modes of control are the actions of protein kinases, whose actions can be direct or indirectly mediated by kinase-modulated protein interactions. Here, we summarize the current state of our understanding of how protein kinases regulate monoamine transporters through changes in activity, trafficking, phosphorylation state, and interacting partners. We highlight genetic, biochemical, and pharmacological evidence for kinase-linked control of DAT, NET, and SERT and, where applicable, provide evidence for endogenous activators of these pathways. We hope our discussion can lead to a more nuanced and integrated understanding of how neurotransmitter transporters are controlled and may contribute to disorders that feature perturbed monoamine signaling, with an ultimate goal of developing better therapeutic strategies.
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Affiliation(s)
- Daniel P Bermingham
- Department of Pharmacology (D.P.B., R.D.B.) and Psychiatry (R.D.B.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Biomedical Sciences, Charles E. Schmidt College of Medicine and Brain Institute, Florida Atlantic University, Jupiter, Florida (R.D.B.)
| | - Randy D Blakely
- Department of Pharmacology (D.P.B., R.D.B.) and Psychiatry (R.D.B.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Biomedical Sciences, Charles E. Schmidt College of Medicine and Brain Institute, Florida Atlantic University, Jupiter, Florida (R.D.B.)
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Jin DC, Cao HL, Xu MQ, Wang SN, Wang YM, Yan F, Wang BM. Regulation of the serotonin transporter in the pathogenesis of irritable bowel syndrome. World J Gastroenterol 2016; 22:8137-8148. [PMID: 27688655 PMCID: PMC5037082 DOI: 10.3748/wjg.v22.i36.8137] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 05/28/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Serotonin (5-HT) and the serotonin transporter (SERT) have earned a tremendous amount of attention regarding the pathogenesis of irritable bowel syndrome (IBS). Considering that enteric 5-HT is responsible for the secretion, motility and perception of the bowel, the involvement of altered enteric 5-HT metabolism in the pathogenesis of IBS has been elucidated. Higher 5-HT availability is commonly associated with depressed SERT mRNA in patients with IBS compared with healthy controls. The expression difference of SERT between IBS patients and healthy controls might suggest that SERT plays an essential role in IBS pathogenesis, and SERT was expected to be a novel therapeutic target for IBS. Progress in this area has begun to illuminate the complex regulatory mechanisms of SERT in the etiology of IBS. In this article, current insights regarding the regulation of SERT in IBS are provided, including aspects of SERT gene polymorphisms, microRNAs, immunity and inflammation, gut microbiota, growth factors, among others. Potential SERT-directed therapies for IBS are also described. The potential regulators of SERT are of clinical importance and are important for better understanding IBS pathophysiology and therapeutic strategies.
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Manoharan A, Shewade DG, Rajkumar RP, Adithan S. Serotonin transporter gene (SLC6A4) polymorphisms are associated with response to fluoxetine in south Indian major depressive disorder patients. Eur J Clin Pharmacol 2016; 72:1215-1220. [DOI: 10.1007/s00228-016-2099-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Accepted: 07/12/2016] [Indexed: 01/08/2023]
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Haberstick BC, Boardman JD, Wagner B, Smolen A, Hewitt JK, Killeya-Jones LA, Tabor J, Halpern CT, Brummett BH, Williams RB, Siegler IC, Hopfer CJ, Mullan Harris K. Depression, Stressful Life Events, and the Impact of Variation in the Serotonin Transporter: Findings from the National Longitudinal Study of Adolescent to Adult Health (Add Health). PLoS One 2016; 11:e0148373. [PMID: 26938215 PMCID: PMC4777542 DOI: 10.1371/journal.pone.0148373] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Accepted: 01/18/2016] [Indexed: 12/16/2022] Open
Abstract
Background The low transcriptionally efficient short-allele of the 5HTTLPR serotonin transporter polymorphism has been implicated to moderate the relationship between the experience of stressful life events (SLEs) and depression. Despite numerous attempts at replicating this observation, results remain inconclusive. Methods We examined this relationship in young-adult Non-Hispanic white males and females between the ages of 22 and 26 (n = 4724) participating in the National Longitudinal Study of Adolescent to Adult Health (Add Health) with follow-up information every six years since 1995. Results Linear and logistic regression models, corrected for multiple testing, indicated that carriers of one or more of the S-alleles were more sensitive to stress than those with two L-alleles and at a higher risk for depression. This relationship behaved in a dose-response manner such that the risk for depression was greatest among those who reported experiencing higher numbers of SLEs. In post-hoc analyses we were not able to replicate an interaction effect for suicide ideation but did find suggestive evidence that the effects of SLEs and 5HTTLPR on suicide ideation differed for males and females. There were no effects of childhood maltreatment. Discussion Our results provide partial support for the original hypothesis that 5-HTTLPR genotype interacts with the experience of stressful life events in the etiology of depression during young adulthood. However, even with this large sample, and a carefully constructed a priori analysis plan, the results were still not definitive. For the purposes of replication, characterizing the 5HTTLPR in other large data sets with extensive environmental and depression measures is needed.
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Affiliation(s)
- Brett C. Haberstick
- Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, Colorado, United States of America
- * E-mail:
| | - Jason D. Boardman
- Institute of Behavioral Science, University of Colorado at Boulder, Boulder, Colorado, United States of America
| | - Brandon Wagner
- Department of Sociology, University of North Carolina, Chapel Hill, North Carolina, United States of America
| | - Andrew Smolen
- Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, Colorado, United States of America
| | - John K. Hewitt
- Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, Colorado, United States of America
| | - Ley A. Killeya-Jones
- Carolina Population Center, University of North Carolina, Chapel Hill, North Carolina, United States of America
| | - Joyce Tabor
- Carolina Population Center, University of North Carolina, Chapel Hill, North Carolina, United States of America
| | - Carolyn T. Halpern
- Carolina Population Center, University of North Carolina, Chapel Hill, North Carolina, United States of America
- Department of Maternal and Child Health, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America
| | - Beverly H. Brummett
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America
| | - Redford B. Williams
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America
| | - Ilene C. Siegler
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America
| | - Christian J. Hopfer
- Department of Psychiatry, Health Sciences Center, University of Colorado, Denver, Colorado, United States of America
| | - Kathleen Mullan Harris
- Department of Sociology, University of North Carolina, Chapel Hill, North Carolina, United States of America
- Carolina Population Center, University of North Carolina, Chapel Hill, North Carolina, United States of America
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Holtmann B, Grosser S, Lagisz M, Johnson SL, Santos ESA, Lara CE, Robertson BC, Nakagawa S. Population differentiation and behavioural association of the two ‘personality’ genesDRD4andSERTin dunnocks (Prunella modularis). Mol Ecol 2016; 25:706-22. [DOI: 10.1111/mec.13514] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 11/25/2015] [Accepted: 11/27/2015] [Indexed: 12/13/2022]
Affiliation(s)
- B. Holtmann
- Department of Zoology; University of Otago; 340 Great King Street Dunedin 9016 New Zealand
| | - S. Grosser
- Department of Zoology; University of Otago; 340 Great King Street Dunedin 9016 New Zealand
| | - M. Lagisz
- Department of Zoology; University of Otago; 340 Great King Street Dunedin 9016 New Zealand
- Evolution & Ecology Research Centre and School of Biological, Earth and Environmental Sciences; University of New South Wales; Sydney NSW 2052 Australia
| | - S. L. Johnson
- Department of Zoology; University of Otago; 340 Great King Street Dunedin 9016 New Zealand
| | - E. S. A. Santos
- Department of Zoology; University of Otago; 340 Great King Street Dunedin 9016 New Zealand
- Departamento de Zoologia; Universidade de São Paulo; Rua do Matão, Trav. 14, n˚ 101 Cid. Universitária São Paulo SP 05508-090 Brazil
| | - C. E. Lara
- Department of Zoology; University of Otago; 340 Great King Street Dunedin 9016 New Zealand
| | - B. C. Robertson
- Department of Zoology; University of Otago; 340 Great King Street Dunedin 9016 New Zealand
| | - S. Nakagawa
- Department of Zoology; University of Otago; 340 Great King Street Dunedin 9016 New Zealand
- Evolution & Ecology Research Centre and School of Biological, Earth and Environmental Sciences; University of New South Wales; Sydney NSW 2052 Australia
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Role of the 5-HTTLPR and SNP Promoter Polymorphisms on Serotonin Transporter Gene Expression: a Closer Look at Genetic Architecture and In Vitro Functional Studies of Common and Uncommon Allelic Variants. Mol Neurobiol 2015; 53:5510-26. [DOI: 10.1007/s12035-015-9409-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 08/23/2015] [Indexed: 12/11/2022]
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Kyzar EJ, Stewart AM, Kalueff AV. Effects of LSD on grooming behavior in serotonin transporter heterozygous (Sert⁺/⁻) mice. Behav Brain Res 2015; 296:47-52. [PMID: 26340513 DOI: 10.1016/j.bbr.2015.08.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 08/11/2015] [Accepted: 08/17/2015] [Indexed: 02/05/2023]
Abstract
Serotonin (5-HT) plays a crucial role in the brain, modulating mood, cognition and reward. The serotonin transporter (SERT) is responsible for the reuptake of 5-HT from the synaptic cleft and regulates serotonin signaling in the brain. In humans, SERT genetic variance is linked to the pathogenesis of various psychiatric disorders, including anxiety, autism spectrum disorders (ASD) and obsessive-compulsive disorder (OCD). Rodent self-grooming is a complex, evolutionarily conserved patterned behavior relevant to stress, ASD and OCD. Genetic ablation of mouse Sert causes various behavioral deficits, including increased anxiety and grooming behavior. The hallucinogenic drug lysergic acid diethylamide (LSD) is a potent serotonergic agonist known to modulate human and animal behavior. Here, we examined heterozygous Sert(+/-) mouse behavior following acute administration of LSD (0.32 mg/kg). Overall, Sert(+/-) mice displayed a longer duration of self-grooming behavior regardless of LSD treatment. In contrast, LSD increased serotonin-sensitive behaviors, such as head twitching, tremors and backwards gait behaviors in both Sert(+/+) and Sert(+/-) mice. There were no significant interactions between LSD treatment and Sert gene dosage in any of the behavioral domains measured. These results suggest that Sert(+/-) mice may respond to the behavioral effects of LSD in a similar manner to wild-type mice.
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Affiliation(s)
- Evan J Kyzar
- Department of Psychiatry, Psychiatric Institute, University of Illinois at Chicago, 1601 W Taylor St, Chicago, IL 60612, USA.
| | | | - Allan V Kalueff
- ZENEREI Institute, 309 Palmer Court, Slidell, LA 70458, USA; Research Institute for Marine Drugs and Nutrition, College for Food Science and Technology, Guangdong Ocean University, Zhanjiang, Guangdong 524025, China; Institute for Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
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Altieri SC, Yang H, O'Brien HJ, Redwine HM, Senturk D, Hensler JG, Andrews AM. Perinatal vs genetic programming of serotonin states associated with anxiety. Neuropsychopharmacology 2015; 40:1456-70. [PMID: 25523893 PMCID: PMC4397404 DOI: 10.1038/npp.2014.331] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 12/05/2014] [Accepted: 12/07/2014] [Indexed: 12/24/2022]
Abstract
Large numbers of women undergo antidepressant treatment during pregnancy; however, long-term consequences for their offspring remain largely unknown. Rodents exposed to serotonin transporter (SERT)-inhibiting antidepressants during development show changes in adult emotion-like behavior. These changes have been equated with behavioral alterations arising from genetic reductions in SERT. Both models are highly relevant to humans yet they vary in their time frames of SERT disruption. We find that anxiety-related behavior and, importantly, underlying serotonin neurotransmission diverge between the two models. In mice, constitutive loss of SERT causes life-long increases in anxiety-related behavior and hyperserotonemia. Conversely, early exposure to the antidepressant escitalopram (ESC; Lexapro) results in decreased anxiety-related behavior beginning in adolescence, which is associated with adult serotonin system hypofunction in the ventral hippocampus. Adult behavioral changes resulting from early fluoxetine (Prozac) exposure were different from those of ESC and, although somewhat similar to SERT deficiency, were not associated with changes in hippocampal serotonin transmission in late adulthood. These findings reveal dissimilarities in adult behavior and neurotransmission arising from developmental exposure to different widely prescribed antidepressants that are not recapitulated by genetic SERT insufficiency. Moreover, they support a pivotal role for serotonergic modulation of anxiety-related behavior.
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Affiliation(s)
- Stefanie C Altieri
- Semel Institute for Neuroscience and Human Behavior and Hatos Center for Neuropharmacology, David Geffen School of Medicine, and California NanoSystems Institute, University of California, Los Angeles, CA, USA
- Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Hongyan Yang
- Semel Institute for Neuroscience and Human Behavior and Hatos Center for Neuropharmacology, David Geffen School of Medicine, and California NanoSystems Institute, University of California, Los Angeles, CA, USA
| | - Hannah J O'Brien
- Semel Institute for Neuroscience and Human Behavior and Hatos Center for Neuropharmacology, David Geffen School of Medicine, and California NanoSystems Institute, University of California, Los Angeles, CA, USA
| | - Hannah M Redwine
- Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX, USA
| | - Damla Senturk
- Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, CA, USA
| | - Julie G Hensler
- Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX, USA
| | - Anne M Andrews
- Semel Institute for Neuroscience and Human Behavior and Hatos Center for Neuropharmacology, David Geffen School of Medicine, and California NanoSystems Institute, University of California, Los Angeles, CA, USA
- Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, USA
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Brennan FX, Gardner KR, Lombard J, Perlis RH, Fava M, Harris HW, Scott R. A Naturalistic Study of the Effectiveness of Pharmacogenetic Testing to Guide Treatment in Psychiatric Patients With Mood and Anxiety Disorders. Prim Care Companion CNS Disord 2015; 17:14m01717. [PMID: 26445691 PMCID: PMC4560190 DOI: 10.4088/pcc.14m01717] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Accepted: 12/22/2014] [Indexed: 10/23/2022] Open
Abstract
OBJECTIVE To examine the effectiveness of genetic testing in a real-world setting and to assess its impact on clinician treatment decisions. METHOD This was a naturalistic, unblinded, prospective analysis of psychiatric patients and clinicians who utilized a commercially available genetic test (between April and October of 2013), which incorporates 10 genes related to pharmacokinetics and pharmacodynamics of psychiatric medications. Each patient's genetic results were provided to participating clinicians, who completed a baseline survey including patient medications, history, and severity of illness. Clinicians were prompted to complete surveys within 1 week of receiving the genetic results and again 3 months later. Patients likewise completed assessments of depression, anxiety, medication side effects, and quality of life at baseline, 1 month, and 3 months. RESULTS Data from 685 patients were collected. Approximately 70% and 29% of patients had primary diagnoses of either a mood or anxiety disorder, respectively. Clinician-reported data, as measured by the Clinical Global Impressions-Improvement scale, indicated that 87% of patients showed clinically measurable improvement (rated as very much improved, much improved, or minimally improved), with 62% demonstrating clinically significant improvement. When analysis was restricted to the 69% of individuals with ≥ 2 prior treatment failures, 91% showed clinically measurable improvement. Patients also reported significant decreases in depression (P < .001), anxiety (P < .001), and medication side effects (P < .001) and increases in quality of life (P < .001). CONCLUSIONS These results suggest that a substantial proportion of individuals receiving pharmacogenetic testing showed clinically significant improvements on multiple measures of symptoms, adverse effects, and quality of life over 3 months. In the absence of a treatment-as-usual comparator, the proportion of improvement attributable to the test cannot be estimated. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01507155.
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Affiliation(s)
- Francis X Brennan
- Genomind, Inc, King of Prussia, Pennsylvania (Drs Brennan, Lombard, and Scott and Ms Gardner); Department of Psychiatry, Massachusetts General Hospital, Boston (Drs Perlis and Fava); and North Carolina Elderly Psychiatric Services, Raleigh (Dr Harris)
| | - Kathryn R Gardner
- Genomind, Inc, King of Prussia, Pennsylvania (Drs Brennan, Lombard, and Scott and Ms Gardner); Department of Psychiatry, Massachusetts General Hospital, Boston (Drs Perlis and Fava); and North Carolina Elderly Psychiatric Services, Raleigh (Dr Harris)
| | - Jay Lombard
- Genomind, Inc, King of Prussia, Pennsylvania (Drs Brennan, Lombard, and Scott and Ms Gardner); Department of Psychiatry, Massachusetts General Hospital, Boston (Drs Perlis and Fava); and North Carolina Elderly Psychiatric Services, Raleigh (Dr Harris)
| | - Roy H Perlis
- Genomind, Inc, King of Prussia, Pennsylvania (Drs Brennan, Lombard, and Scott and Ms Gardner); Department of Psychiatry, Massachusetts General Hospital, Boston (Drs Perlis and Fava); and North Carolina Elderly Psychiatric Services, Raleigh (Dr Harris)
| | - Maurizio Fava
- Genomind, Inc, King of Prussia, Pennsylvania (Drs Brennan, Lombard, and Scott and Ms Gardner); Department of Psychiatry, Massachusetts General Hospital, Boston (Drs Perlis and Fava); and North Carolina Elderly Psychiatric Services, Raleigh (Dr Harris)
| | - Herbert W Harris
- Genomind, Inc, King of Prussia, Pennsylvania (Drs Brennan, Lombard, and Scott and Ms Gardner); Department of Psychiatry, Massachusetts General Hospital, Boston (Drs Perlis and Fava); and North Carolina Elderly Psychiatric Services, Raleigh (Dr Harris)
| | - Rachel Scott
- Genomind, Inc, King of Prussia, Pennsylvania (Drs Brennan, Lombard, and Scott and Ms Gardner); Department of Psychiatry, Massachusetts General Hospital, Boston (Drs Perlis and Fava); and North Carolina Elderly Psychiatric Services, Raleigh (Dr Harris)
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49
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Juhasz G, Gonda X, Hullam G, Eszlari N, Kovacs D, Lazary J, Pap D, Petschner P, Elliott R, Deakin JFW, Anderson IM, Antal P, Lesch KP, Bagdy G. Variability in the effect of 5-HTTLPR on depression in a large European population: the role of age, symptom profile, type and intensity of life stressors. PLoS One 2015; 10:e0116316. [PMID: 25747798 PMCID: PMC4351953 DOI: 10.1371/journal.pone.0116316] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 12/08/2014] [Indexed: 01/01/2023] Open
Abstract
Background Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity. Methods In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models. Results The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (≤30) individuals. Limitations Our study is cross-sectional and applies self-report questionnaires. Conclusions Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups.
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Affiliation(s)
- Gabriella Juhasz
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
- Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, United Kingdom, and Manchester Academic Health Sciences Centre, Manchester, United Kingdom
- * E-mail:
| | - Xenia Gonda
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
- Department of Clinical and Theoretical Mental Health, Kutvolgyi Clinical Center, Semmelweis University, Budapest, Hungary
| | - Gabor Hullam
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
- Department of Measurement and Information Systems, Budapest University of Technology and Economics, Budapest, Hungary
| | - Nora Eszlari
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
| | - David Kovacs
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
| | - Judit Lazary
- Department of Clinical and Theoretical Mental Health, Kutvolgyi Clinical Center, Semmelweis University, Budapest, Hungary
| | - Dorottya Pap
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
| | - Peter Petschner
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
| | - Rebecca Elliott
- Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, United Kingdom, and Manchester Academic Health Sciences Centre, Manchester, United Kingdom
| | - John Francis William Deakin
- Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, United Kingdom, and Manchester Academic Health Sciences Centre, Manchester, United Kingdom
| | - Ian Muir Anderson
- Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, United Kingdom, and Manchester Academic Health Sciences Centre, Manchester, United Kingdom
| | - Peter Antal
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
- Department of Measurement and Information Systems, Budapest University of Technology and Economics, Budapest, Hungary
| | - Klaus-Peter Lesch
- Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany, and Department of Translational Neuroscience, School of Mental Health and Neuroscience (MHENS), Maastricht University, Maastricht, The Netherlands
| | - Gyorgy Bagdy
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
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50
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The potential utility of pharmacogenetic testing in psychiatry. PSYCHIATRY JOURNAL 2014; 2014:730956. [PMID: 25587529 PMCID: PMC4281386 DOI: 10.1155/2014/730956] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Accepted: 11/23/2014] [Indexed: 12/14/2022]
Abstract
Over the last decade, pharmacogenetics has become increasingly significant to clinical practice. Psychiatric patients, in particular, may benefit from pharmacogenetic testing as many of the psychotropic medications prescribed in practice lead to varied response rates and a wide range of side effects. The use of pharmacogenetic testing can help tailor psychotropic treatment and inform personalized treatment plans with the highest likelihood of success. Recently, many studies have been published demonstrating improved patient outcomes and decreased healthcare costs for psychiatric patients who utilize genetic testing. This review will describe evidence supporting the clinical utility of genetic testing in psychiatry, present several case studies to demonstrate use in everyday practice, and explore current patient and clinician opinions of genetic testing.
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