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Song JQ, Xin W, Yu JJ, Zhao Q, Li HN, Chen DC. Neuropeptide Y in first-episode schizophrenia: is there any sex differences in the pathogeneses of schizophrenia? Front Psychiatry 2024; 15:1514475. [PMID: 39691787 PMCID: PMC11649640 DOI: 10.3389/fpsyt.2024.1514475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 11/15/2024] [Indexed: 12/19/2024] Open
Abstract
Objective This study investigated relationships between Neuropeptide Y levels and severity of psychiatric symptoms in first-episode schizophrenia patients, and explore the sexual heterogeneity in them. Methods We recruited 115 first-episode schizophrenia patients and 58 matched healthy controls, and measured serum Neuropeptide Y levels of them at baseline and again after 10 weeks of risperidone treatment in patient group. Patients were also evaluated with the Positive and Negative Symptoms Scale (PANSS) to reveal the severity of symptoms. Results 95 patients completed the whole experiment. We find that mean Neuropeptide Y levels at baseline were significantly higher in patients than in controls (p<0.001), no matter in males or females. In males, there are positive correlations between Neuropeptide Y levels and PANSS scores at baseline (p<0.01), and between the change of them (p<0.05). However, we do not find these correlations in female patients. Furthermore, the interaction terms of NPY × sex were highly significant taking PANSS as dependent variable(p<0.001). Conclusion Neuropeptide Y plays a significant role in the pathogenesis of schizophrenia. In male patients, Neuropeptide Y is positively correlated with the severity of symptoms, while this correlation is not found in females. Continued efforts are needed to determine the sexual dimorphism in pathogeneses of schizophrenia.
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Affiliation(s)
- Jia-Qi Song
- Departments of General Psychiatry, Beijing Huilongguan Hospital, Beijing, China
| | - Wen Xin
- Peking University Huilongguan Clinical Medical School, Beijing, China
| | - Jian-Jin Yu
- Departments of General Psychiatry, Beijing Huilongguan Hospital, Beijing, China
| | - Qing Zhao
- Peking University Huilongguan Clinical Medical School, Beijing, China
| | - Hong-Na Li
- Peking University Huilongguan Clinical Medical School, Beijing, China
| | - Da-Chun Chen
- Departments of General Psychiatry, Beijing Huilongguan Hospital, Beijing, China
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2
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Satao KS, Doshi GM. Anxiety and the brain: Neuropeptides as emerging factors. Pharmacol Biochem Behav 2024; 245:173878. [PMID: 39284499 DOI: 10.1016/j.pbb.2024.173878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 08/23/2024] [Accepted: 09/09/2024] [Indexed: 09/21/2024]
Abstract
Anxiety disorders are characterized by intense feelings of worry and fear, which can significantly interfere with daily functioning. Current treatment options primarily include selective serotonin reuptake inhibitors, benzodiazepines, non-benzodiazepine anxiolytics, gabapentinoids, and beta-blockers. Neuropeptides have shown an important role in the regulation of complex behaviours, such as psychopathology and anxiety-related reactions. Neuropeptides have a great deal of promise to advance our understanding of and ability to help people with anxiety disorders. This review focuses on the expanding role of neuropeptides in anxiety management, particularly examining the impact of substance P, neuropeptide Y, corticotropin-releasing hormone, arginine-vasopressin, pituitary adenylate cyclase-activating polypeptide, and cholecystokinin. Furthermore, the paper discusses the neuropeptides that are becoming more and more recognized for their impact on anxiety-related reactions and their potential as therapeutic targets.
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Affiliation(s)
- Kiran S Satao
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V. M. Road, Vile Parle (W), Mumbai 400 056, Maharashtra, India
| | - Gaurav M Doshi
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V. M. Road, Vile Parle (W), Mumbai 400 056, Maharashtra, India.
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3
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Ma D, Gu C. Discovering functional interactions among schizophrenia-risk genes by combining behavioral genetics with cell biology. Neurosci Biobehav Rev 2024; 167:105897. [PMID: 39278606 PMCID: PMC12057806 DOI: 10.1016/j.neubiorev.2024.105897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 08/26/2024] [Accepted: 09/13/2024] [Indexed: 09/18/2024]
Abstract
Despite much progress in identifying risk genes for polygenic brain disorders, their core pathogenic mechanisms remain poorly understood. In particular, functions of many proteins encoded by schizophrenia risk genes appear diverse and unrelated, complicating the efforts to establish the causal relationship between genes and behavior. Using various mouse lines, recent studies indicate that alterations of parvalbumin-positive (PV+) GABAergic interneurons can lead to schizophrenia-like behavior. PV+ interneurons display fast spiking and contribute to excitation-inhibition balance and network oscillations via feedback and feedforward inhibition. Here, we first summarize different lines of genetically modified mice that display motor, cognitive, emotional, and social impairments used to model schizophrenia and related mental disorders. We highlight ten genes, encoding either a nuclear, cytosolic, or membrane protein. Next, we discuss their functional relationship in regulating fast spiking and other aspects of PV+ interneurons and in the context of other domains of schizophrenia. Future investigations combining behavioral genetics and cell biology should elucidate functional relationships among risk genes to identify the core pathogenic mechanisms underlying polygenic brain disorders.
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Affiliation(s)
- Di Ma
- Ohio State Biochemistry Graduate Program, The Ohio State University, Columbus, OH 43210, USA
| | - Chen Gu
- Ohio State Biochemistry Graduate Program, The Ohio State University, Columbus, OH 43210, USA; Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43210, USA.
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4
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Chen YN, Kostka JK. Beyond anosmia: olfactory dysfunction as a common denominator in neurodegenerative and neurodevelopmental disorders. Front Neurosci 2024; 18:1502779. [PMID: 39539496 PMCID: PMC11557544 DOI: 10.3389/fnins.2024.1502779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
Olfactory dysfunction has emerged as a hallmark feature shared among several neurological conditions, including both neurodevelopmental and neurodegenerative disorders. While diseases of both categories have been extensively studied for decades, their association with olfaction has only recently gained attention. Olfactory deficits often manifest already during prodromal stages of these diseases, yet it remains unclear whether common pathophysiological changes along olfactory pathways cause such impairments. Here we probe into the intricate relationship between olfactory dysfunction and neurodegenerative and neurodevelopmental disorders, shedding light on their commonalities and underlying mechanisms. We begin by providing a brief overview of the olfactory circuit and its connections to higher-associated brain areas. Additionally, we discuss olfactory deficits in these disorders, focusing on potential common mechanisms that may contribute to olfactory dysfunction across both types of disorders. We further debate whether olfactory deficits contribute to the disease propagation or are simply an epiphenomenon. We conclude by emphasizing the significance of olfactory function as a potential pre-clinical diagnostic tool to identify individuals with neurological disorders that offers the opportunity for preventive intervention before other symptoms manifest.
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Affiliation(s)
- Yu-Nan Chen
- Institute of Developmental Neuroscience, Center of Molecular Neurobiology, Hamburg Center of Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johanna Katharina Kostka
- Institute of Developmental Neuroscience, Center of Molecular Neurobiology, Hamburg Center of Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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5
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Doobin DJ, Helmer P, Carabalona A, Bertipaglia C, Vallee RB. The Role of Nde1 phosphorylation in interkinetic nuclear migration and neural migration during cortical development. Mol Biol Cell 2024; 35:ar129. [PMID: 39167527 PMCID: PMC11481692 DOI: 10.1091/mbc.e24-05-0217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 07/18/2024] [Accepted: 08/14/2024] [Indexed: 08/23/2024] Open
Abstract
Nde1 is a cytoplasmic dynein regulatory protein with important roles in vertebrate brain development. One noteworthy function is in the nuclear oscillatory behavior in neural progenitor cells, the control and mechanism of which remain poorly understood. Nde1 contains multiple phosphorylation sites for the cell cycle-dependent protein kinase CDK1, though the function of these sites is not well understood. To test their role in brain development, we expressed phosphorylation-state mutant forms of Nde1 in embryonic rat brains using in utero electroporation. We find that Nde1 T215 and T243 phosphomutants block apical interkinetic nuclear migration (INM) and, consequently, mitosis in radial glial progenitor cells. Another Nde1 phosphomutant at T246 also interfered with mitotic entry without affecting INM, suggesting a more direct role for Nde1 T246 in mitotic regulation. We also found that the Nde1 S214F mutation, which is associated with schizophrenia, inhibits Cdk5 phosphorylation at an adjacent residue which causes alterations in neuronal lamination. These results together identify important new roles for Nde1 phosphorylation in neocortical development and disease, and represent the first evidence for Nde1 phosphorylation roles in INM and neuronal lamination.
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Affiliation(s)
| | - Paige Helmer
- Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY
| | - Aurelie Carabalona
- Institute of Mediterranean Neurobiology, Aix-Marseille University, Marseille, France
| | | | - Richard B. Vallee
- Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY
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6
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Zaharija B, Bradshaw NJ. Aggregation of Disrupted in Schizophrenia 1 arises from a central region of the protein. Prog Neuropsychopharmacol Biol Psychiatry 2024; 130:110923. [PMID: 38135095 DOI: 10.1016/j.pnpbp.2023.110923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 12/12/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023]
Abstract
An emerging approach to studying major mental illness is through proteostasis, with the identification of several proteins that form insoluble aggregates in the brains of patients. One of these is Disrupted in Schizophrenia 1 (DISC1), a neurodevelopmentally-important scaffold protein, and product of a classic schizophrenia risk gene. DISC1 aggregates have been detected in post mortem brain tissue from patients with schizophrenia, bipolar disorder and major depressive disorder, as well as various model systems, although the mechanism by which it aggregates is still unclear. Aggregation of two other proteins implicated in mental illness, TRIOBP-1 and NPAS3, was shown to be dependent on very specific structural regions of the protein. We therefore looked at the domain structure of DISC1, and investigated which structural elements are key for its aggregation. While none of the known structured DISC1 regions (named D, I, S and C respectively) formed aggregates individually when expressed in neuroblastoma cells, the combination of the D and I regions, plus the linker region between them, formed visible aggregates. Further refinement revealed that a region of approximately 30 amino acids between these two regions is critical for aggregation, and deletion of this region is sufficient to abolish the aggregation propensity of DISC1. This finding from mammalian cell culture contrasts with the recent determination that the C-region of DISC1 can aggregate in vitro, although some variations of the C-terminal of DISC1 could aggregate in our system. It therefore appears likely that DISC1 aggregation, implicated in mental illness, can occur through at least two distinct mechanisms.
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Affiliation(s)
- Beti Zaharija
- Faculty of Biotechnology and Drug Development, University of Rijeka, Croatia
| | - Nicholas J Bradshaw
- Faculty of Biotechnology and Drug Development, University of Rijeka, Croatia.
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7
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Hamilton HK, Mathalon DH, Ford JM. P300 in schizophrenia: Then and now. Biol Psychol 2024; 187:108757. [PMID: 38316196 PMCID: PMC11686549 DOI: 10.1016/j.biopsycho.2024.108757] [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: 08/24/2023] [Revised: 01/23/2024] [Accepted: 01/23/2024] [Indexed: 02/07/2024]
Abstract
The 1965 discovery of the P300 component of the electroencephalography (EEG)-based event-related potential (ERP), along with the subsequent identification of its alteration in people with schizophrenia, initiated over 50 years of P300 research in schizophrenia. Here, we review what we now know about P300 in schizophrenia after nearly six decades of research. We describe recent efforts to expand our understanding of P300 beyond its sensitivity to schizophrenia itself to its potential role as a biomarker of risk for psychosis or a heritable endophenotype that bridges genetic risk and psychosis phenomenology. We also highlight efforts to move beyond a syndrome-based approach to understand P300 within the context of the clinical, cognitive, and presumed pathophysiological heterogeneity among people diagnosed with schizophrenia. Finally, we describe several recent approaches that extend beyond measuring the traditional P300 ERP component in people with schizophrenia, including time-frequency analyses and pharmacological challenge studies, that may help to clarify specific cognitive mechanisms that are disrupted in schizophrenia. Moreover, we discuss several promising areas for future research, including studies of animal models that can be used for treatment development.
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Affiliation(s)
- Holly K Hamilton
- University of Minnesota, Department of Psychiatry & Behavioral Sciences, Minneapolis, MN, USA; Minneapolis Veterans Affairs Health Care System, Minneapolis, MN, USA; University of California, San Francisco, Department of Psychiatry & Behavioral Sciences, San Francisco, CA, USA; San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA.
| | - Daniel H Mathalon
- University of California, San Francisco, Department of Psychiatry & Behavioral Sciences, San Francisco, CA, USA; San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA
| | - Judith M Ford
- University of California, San Francisco, Department of Psychiatry & Behavioral Sciences, San Francisco, CA, USA; San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA
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8
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Chau KM, Dominic A, Davis EL, Kotla S, Berrios ET, Fahim A, Arunesh A, Li S, Zhao D, Chen K, Davis AR, Nguyen MTH, Wang Y, Evans SE, Wang G, Cooke JP, Abe JI, Huston DP, Le NT. TNIK regulation of interferon signaling and endothelial cell response to virus infection. Front Cardiovasc Med 2024; 10:1213428. [PMID: 38264262 PMCID: PMC10803426 DOI: 10.3389/fcvm.2023.1213428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 11/27/2023] [Indexed: 01/25/2024] Open
Abstract
Background Traf2 and Nck-interacting kinase (TNIK) is known for its regulatory role in various processes within cancer cells. However, its role within endothelial cells (ECs) has remained relatively unexplored. Methods Leveraging RNA-seq data and Ingenuity Pathway Analysis (IPA), we probed the potential impact of TNIK depletion on ECs. Results Examination of RNA-seq data uncovered more than 450 Differentially Expressed Genes (DEGs) in TNIK-depleted ECs, displaying a fold change exceeding 2 with a false discovery rate (FDR) below 0.05. IPA analysis unveiled that TNIK depletion leads to the inhibition of the interferon (IFN) pathway [-log (p-value) >11], downregulation of IFN-related genes, and inhibition of Hypercytokinemia/Hyperchemokinemia [-log (p-value) >8]. The validation process encompassed qRT-PCR to evaluate mRNA expression of crucial IFN-related genes, immunoblotting to gauge STAT1 and STAT2 protein levels, and ELISA for the quantification of IFN and cytokine secretion in siTNIK-depleted ECs. These assessments consistently revealed substantial reductions upon TNIK depletion. When transducing HUVECs with replication incompetent E1-E4 deleted adenovirus expressing green fluorescent protein (Ad-GFP), it was demonstrated that TNIK depletion did not affect the uptake of Ad-GFP. Nonetheless, TNIK depletion induced cytopathic effects (CPE) in ECs transduced with wild-type human adenovirus serotype 5 (Ad-WT). Summary Our findings suggest that TNIK plays a crucial role in regulating the EC response to virus infections through modulation of the IFN pathway.
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Affiliation(s)
- Khanh M. Chau
- Department of Cardiovascular Sciences, Center for Cardiovascular Sciences, Academic Institute, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, United States
| | - Abishai Dominic
- Department of Cardiovascular Sciences, Center for Cardiovascular Sciences, Academic Institute, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, United States
- Department of Molecular and Cellular Medicine, College of Medicine Texas A&M University, College Station, TX, United States
| | - Eleanor L. Davis
- Center for Cell and Gene Therapy, Baylor College of Medicine, College Station, TX, United States
| | - Sivareddy Kotla
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Estefani Turcios Berrios
- Department of Cardiovascular Sciences, Center for Cardiovascular Sciences, Academic Institute, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, United States
| | - Arsany Fahim
- Center for Cell and Gene Therapy, Baylor College of Medicine, College Station, TX, United States
| | - Ashwin Arunesh
- Center for Cell and Gene Therapy, Baylor College of Medicine, College Station, TX, United States
| | - Shengyu Li
- Department of Cardiovascular Sciences, Center for Cardiovascular Sciences, Academic Institute, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, United States
| | - Dongyu Zhao
- Department of Molecular and Cellular Medicine, College of Medicine Texas A&M University, College Station, TX, United States
| | - Kaifu Chen
- Department of Cardiovascular Sciences, Center for Cardiovascular Sciences, Academic Institute, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, United States
| | - Alan R. Davis
- Center for Cell and Gene Therapy, Baylor College of Medicine, College Station, TX, United States
- Department of Cellular and Molecular Biology, Baylor College of Medicine, Houston, TX, United States
- Department of Orthopedic Surgery, Baylor College of Medicine, Houston, TX, United States
| | - Minh T. H. Nguyen
- Department of Cardiovascular Sciences, Center for Cardiovascular Sciences, Academic Institute, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, United States
| | - Yongxing Wang
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Scott E. Evans
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Guangyu Wang
- Department of Cardiovascular Sciences, Center for Cardiovascular Sciences, Academic Institute, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, United States
| | - John P. Cooke
- Department of Cardiovascular Sciences, Center for Cardiovascular Sciences, Academic Institute, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, United States
| | - Jun-ichi Abe
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - David P. Huston
- Department of Microbial Pathogenesis and Immunology, College of Medicine Texas A&M University, College Station, Houston, TX, United States
| | - Nhat-Tu Le
- Department of Cardiovascular Sciences, Center for Cardiovascular Sciences, Academic Institute, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, United States
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Zhang Z, Wang X, Park S, Song H, Ming GL. Development and Application of Brain Region-Specific Organoids for Investigating Psychiatric Disorders. Biol Psychiatry 2023; 93:594-605. [PMID: 36759261 PMCID: PMC9998354 DOI: 10.1016/j.biopsych.2022.12.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 11/14/2022] [Accepted: 12/12/2022] [Indexed: 12/25/2022]
Abstract
Human society has been burdened by psychiatric disorders throughout the course of its history. The emergence and rapid advances of human brain organoid technology provide unprecedented opportunities for investigation of potential disease mechanisms and development of targeted or even personalized treatments for various psychiatric disorders. In this review, we summarize recent advances for generating organoids from human pluripotent stem cells to model distinct brain regions and diverse cell types. We also highlight recent progress, discuss limitations, and propose potential improvements in using patient-derived or genetically engineered brain region-specific organoids for investigating various psychiatric disorders.
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Affiliation(s)
- Zhijian Zhang
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Xin Wang
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sean Park
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Hongjun Song
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Guo-Li Ming
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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10
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Yaghoubzad-Maleki M, Habibi S, Heshmati E, Khalifeh K. Bioinformatics and Molecular Dynamics Studies on the Human DISC1 in Complex with the Ndel1. JOURNAL OF COMPUTATIONAL BIOPHYSICS AND CHEMISTRY 2023; 22:147-156. [DOI: 10.1142/s2737416523500084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
In this study we analyzed the sequence and structure of the human DISC1-Ndel1 complex using bioinformatics tools and molecular dynamics simulation studies. Multiple sequence alignment between the homologue protein sequences in primates shows that corresponding positions of residues in Ndel1 are highly conserved, while the DISC1 has variable conservation lines demonstrating its tolerability against various mutations during evolutionary time scale. In comparison with the mouse variant, structural analysis has shown that the evolutionary inserted charged residues in the human DISC1 (E[Formula: see text]-R[Formula: see text]) can establish intra-chain electrostatic interactions with the K[Formula: see text]-E[Formula: see text] dipeptide that may result in more stability of the DISC1 chain. According to MD simulation studies, the compactness for the human variant of the DISC1-Ndel1 is considerably lower than that of the mouse variant. Analysis of structural fluctuation shows that a fragment at the N-terminus side of the human DISC1 has more residual fluctuation. However, the Ndel1 chain of the human variant has globally more flexibility compared with the mouse variant. Considering the identical amino acid sequence of the Ndel1 chains of human and mouse, it concluded that there is a competition between the inter-chain and intra-chain electrostatic interaction in the human DISC1 that directs the complex to weaker inter-chain interactions with the expense of strengthening the intra-chain stabilizing interaction in complex.
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Affiliation(s)
| | - Saba Habibi
- Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran
| | - Emran Heshmati
- Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran
| | - Khosrow Khalifeh
- Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran
- Department of Biotechnology, Research Institute of Modern Biological Techniques, University of Zanjan, Zanjan, Iran
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11
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Wilkes SL, Ross DA. The Boy in the Borstal: Gene Hunting, Dopaminergic Dogma, and the Science of Schizophrenia. Biol Psychiatry 2023; 93:e7-e9. [PMID: 36653109 DOI: 10.1016/j.biopsych.2022.11.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 11/17/2022] [Accepted: 11/21/2022] [Indexed: 01/18/2023]
Affiliation(s)
- Sean L Wilkes
- Department of Behavioral Health, Tripler Army Medical Center, Honolulu, Hawaii; Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
| | - David A Ross
- Department of Psychiatry, University of Alberta Faculty of Medicine and Dentistry, Edmonton, Alberta, Canada
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12
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Synaptic plasticity in Schizophrenia pathophysiology. IBRO Neurosci Rep 2023. [DOI: 10.1016/j.ibneur.2023.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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13
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de Sousa TR, Dt C, Novais F. Exploring the Hypothesis of a Schizophrenia and Bipolar Disorder Continuum: Biological, Genetic and Pharmacologic Data. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2023; 22:161-171. [PMID: 34477537 DOI: 10.2174/1871527320666210902164235] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 07/19/2021] [Accepted: 08/08/2021] [Indexed: 12/16/2022]
Abstract
Present time nosology has its roots in Kraepelin's demarcation of schizophrenia and bipolar disorder. However, accumulating evidence has shed light on several commonalities between the two disorders, and some authors have advocated for the consideration of a disease continuum. Here, we review previous genetic, biological and pharmacological findings that provide the basis for this conceptualization. There is a cross-disease heritability, and they share single-nucleotide polymorphisms in some common genes. EEG and imaging patterns have a number of similarities, namely reduced white matter integrity and abnormal connectivity. Dopamine, serotonin, GABA and glutamate systems have dysfunctional features, some of which are identical among the disorders. Finally, cellular calcium regulation and mitochondrial function are, also, impaired in the two.
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Affiliation(s)
- Teresa Reynolds de Sousa
- Department of Neurosciences and Mental Health, Centro Hospitalar Universitário Lisboa Norte (CHULN), Hospital de Santa Maria, Lisbon, Portugal
| | - Correia Dt
- Department of Neurosciences and Mental Health, Centro Hospitalar Universitário Lisboa Norte (CHULN), Hospital de Santa Maria, Lisbon, Portugal
- Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
- ISAMB - Instituto de Saúde Ambiental, Lisboa, Portugal
| | - Filipa Novais
- Department of Neurosciences and Mental Health, Centro Hospitalar Universitário Lisboa Norte (CHULN), Hospital de Santa Maria, Lisbon, Portugal
- Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
- ISAMB - Instituto de Saúde Ambiental, Lisboa, Portugal
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14
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Khan AQ, Thielen L, Le Pen G, Krebs MO, Kebir O, Groh A, Deest M, Bleich S, Frieling H, Jahn K. Methylation pattern and mRNA expression of synapse-relevant genes in the MAM model of schizophrenia in the time-course of adolescence. SCHIZOPHRENIA (HEIDELBERG, GERMANY) 2022; 8:110. [PMID: 36481661 PMCID: PMC9732294 DOI: 10.1038/s41537-022-00319-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 11/16/2022] [Indexed: 12/13/2022]
Abstract
Schizophrenia is highly heritable and aggregating in families, but genetics alone does not exclusively explain the pathogenesis. Many risk factors, including childhood trauma, viral infections, migration, and the use of cannabis, are associated with schizophrenia. Adolescence seems to be the critical period where symptoms of the disease manifest. This work focuses on studying an epigenetic regulatory mechanism (the role of DNA methylation) and its interaction with mRNA expression during development, with a particular emphasis on adolescence. The presumptions regarding the role of aberrant neurodevelopment in schizophrenia were tested in the Methyl-Azoxy-Methanol (MAM) animal model. MAM treatment induces neurodevelopmental disruptions and behavioral deficits in off-springs of the treated animals reminiscent of those observed in schizophrenia and is thus considered a promising model for studying this pathology. On a gestational day-17, adult pregnant rats were treated with the antimitotic agent MAM. Experimental animals were divided into groups and subgroups according to substance treatment (MAM and vehicle agent [Sham]) and age of analysis (pre-adolescent and post-adolescent). Methylation and mRNA expression analysis of four candidate genes, which are often implicated in schizophrenia, with special emphasis on the Dopamine hypothesis i.e., Dopamine receptor D2 (Drd2), and the "co-factors" Disrupted in schizophrenia 1 (DISC1), Synaptophysin (Syp), and Dystrobrevin-binding protein 1 (Dtnbp1), was performed in the Gyrus cingulum (CING) and prefrontal cortex (PFC). Data were analyzed to observe the effect of substance treatment between groups and the impact of adolescence within-group. We found reduced pre-adolescent expression levels of Drd2 in both brain areas under the application of MAM. The "co-factor genes" did not show high deviations in mRNA expression levels but high alterations of methylation rates under the application of MAM (up to ~20%), which diminished in the further time course, reaching a comparable level like in Sham control animals after adolescence. The pre-adolescent reduction in DRD2 expression might be interpreted as downregulation of the receptor due to hyperdopaminergic signaling from the ventral tegmental area (VTA), eventually even to both investigated brain regions. The notable alterations of methylation rates in the three analyzed co-factor genes might be interpreted as attempt to compensate for the altered dopaminergic neurotransmission.
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Affiliation(s)
- Abdul Qayyum Khan
- grid.10423.340000 0000 9529 9877Laboratory for Molecular Neurosciences (LMN), Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover (MHH), Carl-Neuberg-Str. 1, 30625 Hannover, Germany ,grid.444940.9University of Management and Technology—School of Pharmacy, 72-A Raiwind Rd, Dubai Town, Lahore Pakistan
| | - Lukas Thielen
- grid.10423.340000 0000 9529 9877Laboratory for Molecular Neurosciences (LMN), Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover (MHH), Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Gwenaëlle Le Pen
- grid.512035.0Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM, Pathophysiology of Psychiatric disorders: Development and Vulnerability, U1266, 102-108 Rue de la Santé, 75014 Paris, France
| | - Marie-Odile Krebs
- grid.512035.0Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM, Pathophysiology of Psychiatric disorders: Development and Vulnerability, U1266, 102-108 Rue de la Santé, 75014 Paris, France ,GHU Paris Psychiatrie et Neurosciences, 1 Rue Cabanis, 75014 Paris, France
| | - Oussama Kebir
- grid.512035.0Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM, Pathophysiology of Psychiatric disorders: Development and Vulnerability, U1266, 102-108 Rue de la Santé, 75014 Paris, France ,GHU Paris Psychiatrie et Neurosciences, 1 Rue Cabanis, 75014 Paris, France
| | - Adrian Groh
- grid.10423.340000 0000 9529 9877Laboratory for Molecular Neurosciences (LMN), Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover (MHH), Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Maximilian Deest
- grid.10423.340000 0000 9529 9877Laboratory for Molecular Neurosciences (LMN), Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover (MHH), Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Stefan Bleich
- grid.10423.340000 0000 9529 9877Laboratory for Molecular Neurosciences (LMN), Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover (MHH), Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Helge Frieling
- grid.10423.340000 0000 9529 9877Laboratory for Molecular Neurosciences (LMN), Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover (MHH), Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Kirsten Jahn
- grid.10423.340000 0000 9529 9877Laboratory for Molecular Neurosciences (LMN), Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover (MHH), Carl-Neuberg-Str. 1, 30625 Hannover, Germany
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15
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Zhang K, Liao P, Wen J, Hu Z. Synaptic plasticity in schizophrenia pathophysiology. IBRO Neurosci Rep 2022; 13:478-487. [PMID: 36590092 PMCID: PMC9795311 DOI: 10.1016/j.ibneur.2022.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 10/21/2022] [Indexed: 11/05/2022] Open
Abstract
Schizophrenia is a severe neuropsychiatric syndrome with psychotic behavioral abnormalities and marked cognitive deficits. It is widely accepted that genetic and environmental factors contribute to the onset of schizophrenia. However, the etiology and pathology of the disease remain largely unexplored. Recently, the synaptopathology and the dysregulated synaptic plasticity and function have emerging as intriguing and prominent biological mechanisms of schizophrenia pathogenesis. Synaptic plasticity is the ability of neurons to change the strength of their connections in response to internal or external stimuli, which is essential for brain development and function, learning and memory, and vast majority of behavior responses relevant to psychiatric diseases including schizophrenia. Here, we reviewed molecular and cellular mechanisms of the multiple forms synaptic plasticity, and the functional regulations of schizophrenia-risk factors including disease susceptible genes and environmental alterations on synaptic plasticity and animal behavior. Recent genome-wide association studies have provided fruitful findings of hundreds of risk gene variances associated with schizophrenia, thus further clarifying the role of these disease-risk genes in synaptic transmission and plasticity will be beneficial to advance our understanding of schizophrenia pathology, as well as the molecular mechanism of synaptic plasticity.
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Affiliation(s)
- Kexuan Zhang
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China,Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410008, Hunan, PR China
| | - Panlin Liao
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China,National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China
| | - Jin Wen
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China,National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China
| | - Zhonghua Hu
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China,Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410008, Hunan, PR China,National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China,Hunan Provincial Clinical Research Center for Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China,Hunan Key Laboratory of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha 410008, Hunan, PR China,Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha 410008, Hunan, PR China,Correspondence to: Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, 87 Xiangya Rd, Changsha, Hunan, PR China.
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16
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Sauer JF, Bartos M. Disrupted-in-schizophrenia-1 is required for normal pyramidal cell-interneuron communication and assembly dynamics in the prefrontal cortex. eLife 2022; 11:79471. [PMID: 36239988 PMCID: PMC9566853 DOI: 10.7554/elife.79471] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 09/29/2022] [Indexed: 11/13/2022] Open
Abstract
We interrogated prefrontal circuit function in mice lacking Disrupted-in-schizophrenia-1 (Disc1-mutant mice), a risk factor for psychiatric disorders. Single-unit recordings in awake mice revealed reduced average firing rates of fast-spiking interneurons (INTs), including optogenetically identified parvalbumin-positive cells, and a lower proportion of INTs phase-coupled to ongoing gamma oscillations. Moreover, we observed decreased spike transmission efficacy at local pyramidal cell (PYR)-INT connections in vivo, suggesting a reduced excitatory effect of local glutamatergic inputs as a potential mechanism of lower INT rates. On the network level, impaired INT function resulted in altered activation of PYR assemblies: While assembly activations defined as coactivations within 25 ms were observed equally often, the expression strength of individual assembly patterns was significantly higher in Disc1-mutant mice. Our data, thus, reveal a role of Disc1 in shaping the properties of prefrontal assembly patterns by setting INT responsiveness to glutamatergic drive.
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Affiliation(s)
- Jonas-Frederic Sauer
- Institute for Physiology I, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Marlene Bartos
- Institute for Physiology I, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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17
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Vouga Ribeiro N, Tavares V, Bramon E, Toulopoulou T, Valli I, Shergill S, Murray R, Prata D. Effects of psychosis-associated genetic markers on brain volumetry: a systematic review of replicated findings and an independent validation. Psychol Med 2022; 52:1-16. [PMID: 36168994 PMCID: PMC9811278 DOI: 10.1017/s0033291722002896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 08/13/2022] [Accepted: 08/24/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND Given psychotic illnesses' high heritability and associations with brain structure, numerous neuroimaging-genetics findings have been reported in the last two decades. However, few findings have been replicated. In the present independent sample we aimed to replicate any psychosis-implicated SNPs (single nucleotide polymorphisms), which had previously shown at least two main effects on brain volume. METHODS A systematic review for SNPs showing a replicated effect on brain volume yielded 25 studies implicating seven SNPs in five genes. Their effect was then tested in 113 subjects with either schizophrenia, bipolar disorder, 'at risk mental state' or healthy state, for whole-brain and region-of-interest (ROI) associations with grey and white matter volume changes, using voxel-based morphometry. RESULTS We found FWER-corrected (Family-wise error rate) (i.e. statistically significant) associations of: (1) CACNA1C-rs769087-A with larger bilateral hippocampus and thalamus white matter, across the whole brain; and (2) CACNA1C-rs769087-A with larger superior frontal gyrus, as ROI. Higher replication concordance with existing literature was found, in decreasing order, for: (1) CACNA1C-rs769087-A, with larger dorsolateral-prefrontal/superior frontal gyrus and hippocampi (both with anatomical and directional concordance); (2) ZNF804A-rs11681373-A, with smaller angular gyrus grey matter and rectus gyri white matter (both with anatomical and directional concordance); and (3) BDNF-rs6265-T with superior frontal and middle cingulate gyri volume change (with anatomical and allelic concordance). CONCLUSIONS Most literature findings were not herein replicated. Nevertheless, high degree/likelihood of replication was found for two genome-wide association studies- and one candidate-implicated SNPs, supporting their involvement in psychosis and brain structure.
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Affiliation(s)
- Nuno Vouga Ribeiro
- Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Biofísica e Engenharia Biomédica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
| | - Vânia Tavares
- Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Biofísica e Engenharia Biomédica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
| | - Elvira Bramon
- Division of Psychiatry, University College London, London, UK
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’ College London, London, UK
- Institute of Cognitive Neuroscience, University College London, London, UK
| | - Timothea Toulopoulou
- Department of Psychology & National Magnetic Resonance Research Center (UMRAM), Aysel Sabuncu Brain Research Centre (ASBAM), Bilkent University, Ankara, Turkey
| | - Isabel Valli
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’ College London, London, UK
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Sukhi Shergill
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’ College London, London, UK
| | - Robin Murray
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’ College London, London, UK
| | - Diana Prata
- Instituto de Biofísica e Engenharia Biomédica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
- Department of Old Age Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
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18
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Heider J, Sperlich D, Vogel S, Breitmeyer R, Volkmer H. Generation of two induced pluripotent stem cell lines (TMOi001-A-5, TMOi001-A-6) carrying variants in DISC1 exon 2 using CRISPR/Cas9 gene editing. Stem Cell Res 2022; 64:102925. [PMID: 36154917 DOI: 10.1016/j.scr.2022.102925] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 09/19/2022] [Indexed: 10/14/2022] Open
Abstract
DISC1 is a scaffold protein involved in key developmental processes such as neuronal migration, differentiation and neurogenesis. Genetic variants of the DISC1 gene have been linked to neuropsychiatric disorders like schizophrenia, bipolar disorder and major depression. Here, we generated two isogenic iPSC lines carrying mutations in DISC1 exon 2 using CRISPR/Cas9 gene editing. Both lines express pluripotency markers, can be differentiated into the three germ layers and present a normal karyotype. The generated iPSC lines can be used to study the implications of DISC1 mutations in the context of neuropsychiatric diseases in vitro.
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Affiliation(s)
- Johanna Heider
- Molecular Biology and Neurobiology, NMI Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770 Reutlingen, Germany
| | - Denise Sperlich
- Molecular Biology and Neurobiology, NMI Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770 Reutlingen, Germany
| | - Sabrina Vogel
- Molecular Biology and Neurobiology, NMI Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770 Reutlingen, Germany
| | - Ricarda Breitmeyer
- Molecular Biology and Neurobiology, NMI Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770 Reutlingen, Germany
| | - Hansjürgen Volkmer
- Molecular Biology and Neurobiology, NMI Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770 Reutlingen, Germany
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19
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Social anhedonia as a Disrupted-in-Schizophrenia 1-dependent phenotype. Sci Rep 2022; 12:10182. [PMID: 35715502 PMCID: PMC9205858 DOI: 10.1038/s41598-022-14102-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 06/01/2022] [Indexed: 11/09/2022] Open
Abstract
Deficits in social interaction or social cognition are key phenotypes in a variety of chronic mental diseases, yet, their modeling and molecular dissection are only in their infancy. The Disrupted-in-Schizophrenia 1 (DISC1) signaling pathway is considered to play a role in different psychiatric disorders such as schizophrenia, depression, and biopolar disorders. DISC1 is involved in regulating the dopaminergic neurotransmission in, among others, the mesolimbic reward system. A transgenic rat line tgDISC1 has been introduced as a model system to study behavioral phenotypes associated with abnormal DISC1 signaling pathways. Here, we evaluated the impact of impaired DISC1 signaling on social (social interaction) and non-social (sucrose) reward preferences in the tgDISC1 animal model. In a plus-maze setting, rats chose between the opportunity for social interaction with an unfamiliar juvenile conspecific (social reward) or drinking sweet solutions with variable sucrose concentrations (non-social reward). tgDISC1 rats differed from wild-type rats in their social, but not in their non-social reward preferences. Specifically, DISC1 rats showed a lower interest in interaction with the juvenile conspecific, but did not differ from wild-type rats in their preference for higher sucrose concentrations. These results suggest that disruptions of the DISC1 signaling pathway that is associated with altered dopamine transmission in the brain result in selective deficits in social motivation reminiscent of phenotypes seen in neuropsychiatric illness.
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20
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Zhang W, Ross PJ, Ellis J, Salter MW. Targeting NMDA receptors in neuropsychiatric disorders by drug screening on human neurons derived from pluripotent stem cells. Transl Psychiatry 2022; 12:243. [PMID: 35680847 PMCID: PMC9184461 DOI: 10.1038/s41398-022-02010-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 05/25/2022] [Accepted: 05/27/2022] [Indexed: 01/04/2023] Open
Abstract
NMDA receptors (NMDARs), a prominent subtype of glutamatergic receptors, are implicated in the pathogenesis and development of neuropsychiatric disorders such as epilepsy, intellectual disability, autism spectrum disorder, and schizophrenia, and are therefore a potential therapeutic target in treating these disorders. Neurons derived from induced pluripotent stem cells (iPSCs) have provided the opportunity to investigate human NMDARs in their native environment. In this review, we describe the expression, function, and regulation of NMDARs in human iPSC-derived neurons and discuss approaches for utilizing human neurons for identifying potential drugs that target NMDARs in the treatment of neuropsychiatric disorders. A challenge in studying NMDARs in human iPSC-derived neurons is a predominance of those receptors containing the GluN2B subunit and low synaptic expression, suggesting a relatively immature phenotype of these neurons and delayed development of functional NMDARs. We outline potential approaches for improving neuronal maturation of human iPSC-derived neurons and accelerating the functional expression of NMDARs. Acceleration of functional expression of NMDARs in human iPSC-derived neurons will improve the modeling of neuropsychiatric disorders and facilitate the discovery and development of novel therapeutics targeting NMDARs for the treatment of these disorders.
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Affiliation(s)
- Wenbo Zhang
- Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada
- Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - P Joel Ross
- Biology Department, University of Prince Edward Island, Charlottetown, PE, C1A 4P3, Canada
| | - James Ellis
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, M5S 1A8, Canada
| | - Michael W Salter
- Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
- Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
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21
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Wang AL, Chao OY, Nikolaus S, Lamounier-Zepter V, Hollenberg CP, Lubec G, Trossbach SV, Korth C, Huston JP. Disrupted-in-schizophrenia 1 Protein Misassembly Impairs Cognitive Flexibility and Social Behaviors in a Transgenic Rat Model. Neuroscience 2022; 493:41-51. [PMID: 35461978 DOI: 10.1016/j.neuroscience.2022.04.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 04/12/2022] [Accepted: 04/13/2022] [Indexed: 11/19/2022]
Abstract
Alterations in cognitive functions, social behaviors and stress reactions are commonly diagnosed in chronic mental illnesses (CMI). Animal models expressing mutant genes associated to CMI represent either rare mutations or those contributing only minimally to genetic risk. Non-genetic causes of CMI can be modeled by disturbing downstream signaling pathways, for example through inducing protein misassembly or aggregation. The Disrupted-in-Schizophrenia 1 (DISC1) gene was identified to be disrupted and thereby haploinsufficient in a large pedigree where it associated to CMI. The DISC1 protein misassembles to an insoluble protein in a subset of CMI patients and this has been modeled in a rat (tgDISC1 rat) where the full-length, non mutant human transgene was overexpressed and cognitive impairments were observed. Here, we investigated the scope of effects of DISC1 protein misassembly by investigating spatial memory, social behavior and stress resilience. In water maze tasks, the tgDISC1 rats showed intact spatial learning and memory, but were deficient in flexible adaptation to spatial reversal learning compared to littermate controls. They also displayed less social interaction. Additionally, there was a trend towards increased corticosterone levels after restraint stress in the tgDISC1 rats. Our findings suggest that DISC1 protein misassembly leads to disturbances of cognitive flexibility and social behaviors, and might also be involved in stress sensitization. Since the observed behavioral features resemble symptoms of CMI, the tgDISC1 rat may be a valuable model for the investigation of cognitive, social and - possibly - also stress-related symptoms of major mental illnesses.
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Affiliation(s)
- An-Li Wang
- Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
| | - Owen Y Chao
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA.
| | - Susanne Nikolaus
- Department of Nuclear Medicine, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany.
| | | | - Cornelis P Hollenberg
- Institute of Microbiology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
| | - Gert Lubec
- Department of Neuroproteomics, Paracelsus Private Medical University, Salzburg, Austria.
| | - Svenja V Trossbach
- Department of Neuropathology, University Hospital Düsseldorf, Düsseldorf, Germany.
| | - Carsten Korth
- Department of Neuropathology, University Hospital Düsseldorf, Düsseldorf, Germany.
| | - Joseph P Huston
- Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
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22
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Recent behavioral findings of pathophysiological involvement of lactate in the central nervous system. Biochim Biophys Acta Gen Subj 2022; 1866:130137. [DOI: 10.1016/j.bbagen.2022.130137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 11/19/2022]
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23
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Hu L, Zhang L. Adult neural stem cells and schizophrenia. World J Stem Cells 2022; 14:219-230. [PMID: 35432739 PMCID: PMC8968214 DOI: 10.4252/wjsc.v14.i3.219] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/18/2021] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia (SCZ) is a devastating and complicated mental disorder accompanied by variable positive and negative symptoms and cognitive deficits. Although many genetic risk factors have been identified, SCZ is also considered as a neurodevelopmental disorder. Elucidation of the pathogenesis and the development of treatment is challenging because complex interactions occur between these genetic risk factors and environment in essential neurodevelopmental processes. Adult neural stem cells share a lot of similarities with embryonic neural stem cells and provide a promising model for studying neuronal development in adulthood. These adult neural stem cells also play an important role in cognitive functions including temporal and spatial memory encoding and context discrimination, which have been shown to be closely linked with many psychiatric disorders, such as SCZ. Here in this review, we focus on the SCZ risk genes and the key components in related signaling pathways in adult hippocampal neural stem cells and summarize their roles in adult neurogenesis and animal behaviors. We hope that this would be helpful for the understanding of the contribution of dysregulated adult neural stem cells in the pathogenesis of SCZ and for the identification of potential therapeutic targets, which could facilitate the development of novel medication and treatment.
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Affiliation(s)
- Ling Hu
- Department of Laboratory Animal Science and Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Lei Zhang
- Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center) and Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai 200092, China
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24
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Exploring the role of neuropeptides in depression and anxiety. Prog Neuropsychopharmacol Biol Psychiatry 2022; 114:110478. [PMID: 34801611 DOI: 10.1016/j.pnpbp.2021.110478] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 11/13/2021] [Accepted: 11/13/2021] [Indexed: 12/24/2022]
Abstract
Depression is one of the most prevalent forms of mental disorders and is the most common cause of disability in the Western world. Besides, the harmful effects of stress-related mood disorders on the patients themselves, they challenge the health care system with enormous social and economic impacts. Due to the high proportion of patients not responding to existing drugs, finding new treatment strategies has become an important topic in neurobiology, and there is much evidence that neuropeptides are not only involved in the physiology of stress but may also be clinically important. Based on preclinical trial data, new neuropharmaceutical candidates may target neuropeptides and their receptors and are expected to be essential and valuable tools in the treatment of psychiatric disorders. In the current article, we have summarized data obtained from animal models of depressive disorder and transgenic mouse models. We also focus on previously published research data of clinical studies on corticotropin-releasing hormone (CRH), galanin (GAL), neuropeptide Y (NPY), neuropeptide S (NPS), Oxytocin (OXT), vasopressin (VP), cholecystokinin (CCK), and melanin-concentrating hormone (MCH) stress research fields.
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25
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Regulation of sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport in the cortico-striatal circuit. Mol Psychiatry 2022; 27:1805-1815. [PMID: 35165396 PMCID: PMC9272458 DOI: 10.1038/s41380-021-01389-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 10/15/2021] [Accepted: 11/03/2021] [Indexed: 11/30/2022]
Abstract
Sensorimotor information processing underlies normal cognitive and behavioral traits and has classically been evaluated through prepulse inhibition (PPI) of a startle reflex. PPI is a behavioral dimension deregulated in several neurological and psychiatric disorders, yet the mechanisms underlying the cross-diagnostic nature of PPI deficits across these conditions remain to be understood. To identify circuitry mechanisms for PPI, we performed circuitry recording over the prefrontal cortex and striatum, two brain regions previously implicated in PPI, using wild-type (WT) mice compared to Disc1-locus-impairment (LI) mice, a model representing neuropsychiatric conditions. We demonstrated that the corticostriatal projection regulates neurophysiological responses during the PPI testing in WT, whereas these circuitry responses were disrupted in Disc1-LI mice. Because our biochemical analyses revealed attenuated brain-derived neurotrophic factor (Bdnf) transport along the corticostriatal circuit in Disc1-LI mice, we investigated the potential role of Bdnf in this circuitry for regulation of PPI. Virus-mediated delivery of Bdnf into the striatum rescued PPI deficits in Disc1-LI mice. Pharmacologically augmenting Bdnf transport by chronic lithium administration, partly via phosphorylation of Huntingtin (Htt) serine-421 and its integration into the motor machinery, restored striatal Bdnf levels and rescued PPI deficits in Disc1-LI mice. Furthermore, reducing the cortical Bdnf expression negated this rescuing effect of lithium, confirming the key role of Bdnf in lithium-mediated PPI rescuing. Collectively, the data suggest that striatal Bdnf supply, collaboratively regulated by Htt and Disc1 along the corticostriatal circuit, is involved in sensorimotor gating, highlighting the utility of dimensional approach in investigating pathophysiological mechanisms across neuropsychiatric disorders.
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Chen YM, Lin CH, Lane HY. Distinctively lower DISC1 mRNA levels in patients with schizophrenia, especially in those with higher positive, negative, and depressive symptoms. Pharmacol Biochem Behav 2022; 213:173335. [PMID: 35033484 DOI: 10.1016/j.pbb.2022.173335] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/06/2022] [Accepted: 01/07/2022] [Indexed: 12/18/2022]
Abstract
BACKGROUND The issue of genetic influence on schizophrenia has received considerable attention. The DISC1 gene has been shown in several studies to play a role in the pathophysiology of schizophrenia. However, the relationship between DISC1 mRNA expression vs. schizophrenia and its clinical symptoms is uncertain. METHODS Fifty-six subjects (32 patients with schizophrenia and 24 healthy controls) were enrolled. Peripheral blood was obtained from all subjects to exam the DISC1 mRNA expression. Schizophrenia patients were evaluated with Hamilton Rating Scale for Depression (HAMD), Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS) and Scale for the Assessment of Negative Symptoms (SANS) scales. Healthy subjects were assessed with HAMD scale. RESULTS Patients with schizophrenia had significantly lower levels of the DISC1 mRNA expression than the healthy control (P = 0.002). We also found that lower DISC1 mRNA levels in schizophrenia patients were associated with higher degree of depression in HAMD (P = 0.037), severer positive symptoms in PANSS (P = 0.032) and more negative symptoms in SANS (P = 0.038). CONCLUSION The results showed that schizophrenia patients had lower levels of DISC1 mRNA than healthy individuals, and that the schizophrenia patients with lower DISC1 mRNA levels were more likely to manifest more marked symptoms, including positive, negative, and depressive symptoms. The findings suggest that lower DISC1 expression may be related with the pathogenesis and phenotypes of schizophrenia. Future studies are needed to replicate the results and to further establish its potential role in clinical application of early diagnosis and outcome follow-up.
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Affiliation(s)
- Yu-Ming Chen
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chieh-Hsin Lin
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; School of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
| | - Hsien-Yuan Lane
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Department of Psychiatry & Brain Disease Research Center, China Medical University Hospital, Taichung, Taiwan; Department of Psychology, College of Medical and Health Sciences, Asia University, Taichung, Taiwan.
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27
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Mutations in DISC1 alter IP 3R and voltage-gated Ca 2+ channel functioning, implications for major mental illness. Neuronal Signal 2021; 5:NS20180122. [PMID: 34956649 PMCID: PMC8663806 DOI: 10.1042/ns20180122] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 10/26/2021] [Accepted: 11/08/2021] [Indexed: 12/16/2022] Open
Abstract
Disrupted in Schizophrenia 1 (DISC1) participates in a wide variety of
developmental processes of central neurons. It also serves critical roles that
underlie cognitive functioning in adult central neurons. Here we summarize
DISC1’s general properties and discuss its use as a model system for
understanding major mental illnesses (MMIs). We then discuss the cellular
actions of DISC1 that involve or regulate Ca2+ signaling in adult
central neurons. In particular, we focus on the tethering role DISC1 plays in
transporting RNA particles containing Ca2+ channel subunit RNAs,
including IP3R1, CACNA1C and CACNA2D1, and in transporting mitochondria into
dendritic and axonal processes. We also review DISC1’s role in modulating
IP3R1 activity within mitochondria-associated ER membrane (MAM).
Finally, we discuss DISC1-glycogen synthase kinase 3β (GSK3β)
signaling that regulates functional expression of voltage-gated Ca2+
channels (VGCCs) at central synapses. In each case, DISC1 regulates the movement
of molecules that impact Ca2+ signaling in neurons.
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Cukkemane A, Becker N, Zielinski M, Frieg B, Lakomek NA, Heise H, Schröder GF, Willbold D, Weiergräber OH. Conformational heterogeneity coupled with β-fibril formation of a scaffold protein involved in chronic mental illnesses. Transl Psychiatry 2021; 11:639. [PMID: 34921141 PMCID: PMC8683410 DOI: 10.1038/s41398-021-01765-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 11/23/2021] [Accepted: 12/07/2021] [Indexed: 12/17/2022] Open
Abstract
Chronic mental illnesses (CMIs) pose a significant challenge to global health due to their complex and poorly understood etiologies and hence, absence of causal therapies. Research of the past two decades has revealed dysfunction of the disrupted in schizophrenia 1 (DISC1) protein as a predisposing factor involved in several psychiatric disorders. DISC1 is a multifaceted protein that serves myriads of functions in mammalian cells, for instance, influencing neuronal development and synapse maintenance. It serves as a scaffold hub forming complexes with a variety (~300) of partners that constitute its interactome. Herein, using combinations of structural and biophysical tools, we demonstrate that the C-region of the DISC1 protein is highly polymorphic, with important consequences for its physiological role. Results from solid-state NMR spectroscopy and electron microscopy indicate that the protein not only forms symmetric oligomers but also gives rise to fibrils closely resembling those found in certain established amyloid proteinopathies. Furthermore, its aggregation as studied by isothermal titration calorimetry (ITC) is an exergonic process, involving a negative enthalpy change that drives the formation of oligomeric (presumably tetrameric) species as well as β-fibrils. We have been able to narrow down the β-core region participating in fibrillization to residues 716-761 of full-length human DISC1. This region is absent in the DISC1Δ22aa splice variant, resulting in reduced association with proteins from the dynein motor complex, viz., NDE-like 1 (NDEL1) and lissencephaly 1 (LIS1), which are crucial during mitosis. By employing surface plasmon resonance, we show that the oligomeric DISC1 C-region has an increased affinity and shows cooperativity in binding to LIS1 and NDEL1, in contrast to the noncooperative binding mode exhibited by the monomeric version. Based on the derived structural models, we propose that the association between the binding partners involves two neighboring subunits of DISC1 C-region oligomers. Altogether, our findings highlight the significance of the DISC1 C-region as a crucial factor governing the balance between its physiological role as a multifunctional scaffold protein and aggregation-related aberrations with potential significance for disease.
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Affiliation(s)
- Abhishek Cukkemane
- Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany. .,Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
| | - Nina Becker
- grid.8385.60000 0001 2297 375XInstitute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany ,grid.411327.20000 0001 2176 9917Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,grid.8385.60000 0001 2297 375XJülich Centre for Structural Biology (JuStruct), Forschungszentrum Jülich, Jülich, Germany
| | - Mara Zielinski
- grid.8385.60000 0001 2297 375XInstitute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany
| | - Benedikt Frieg
- grid.8385.60000 0001 2297 375XInstitute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany
| | - Nils-Alexander Lakomek
- grid.8385.60000 0001 2297 375XInstitute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany ,grid.411327.20000 0001 2176 9917Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,grid.8385.60000 0001 2297 375XJülich Centre for Structural Biology (JuStruct), Forschungszentrum Jülich, Jülich, Germany
| | - Henrike Heise
- grid.8385.60000 0001 2297 375XInstitute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany ,grid.411327.20000 0001 2176 9917Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,grid.8385.60000 0001 2297 375XJülich Centre for Structural Biology (JuStruct), Forschungszentrum Jülich, Jülich, Germany
| | - Gunnar F. Schröder
- grid.8385.60000 0001 2297 375XInstitute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany ,grid.8385.60000 0001 2297 375XJülich Centre for Structural Biology (JuStruct), Forschungszentrum Jülich, Jülich, Germany ,grid.411327.20000 0001 2176 9917Physics Department, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Dieter Willbold
- Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany. .,Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. .,Jülich Centre for Structural Biology (JuStruct), Forschungszentrum Jülich, Jülich, Germany.
| | - Oliver H. Weiergräber
- grid.8385.60000 0001 2297 375XInstitute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany ,grid.8385.60000 0001 2297 375XJülich Centre for Structural Biology (JuStruct), Forschungszentrum Jülich, Jülich, Germany
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Gao Y, Li Y, Li S, Liang X, Ren Z, Yang X, Zhang B, Hu Y, Yang X. Systematic discovery of signaling pathways linking immune activation to schizophrenia. iScience 2021; 24:103209. [PMID: 34746692 PMCID: PMC8551081 DOI: 10.1016/j.isci.2021.103209] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 06/21/2021] [Accepted: 09/29/2021] [Indexed: 11/06/2022] Open
Abstract
Immune activation has been shown to play a critical role in the development of schizophrenia; however its underlying mechanism remains unknown. Our report demonstrates a high-quality protein interaction network for schizophrenia (SCZ Network), constructed using our “neighborhood walk” approach in combination with “random walk with restart”. The spatiotemporal expression pattern of the genes in this disease network revealed two developmental stages sensitive to perturbation by immune activation: mid-to late gestation, and adolescence. Furthermore, we induced immune activation at these stages in mice, carried out transcriptome sequencing on the mouse brains, and illustrated clear potential molecular pathways and key regulators correlating maternal immune activation during gestation and an increased risk for schizophrenia after a second immune activation at puberty. This work provides not only valuable resources for the study on molecular mechanisms underlying schizophrenia, but also a systematic strategy for the discovery of molecular pathways of complex mental disorders.
A high-quality molecular network for schizophrenia (SCZ Network) A landscape of molecular pathways linking immune activation and schizophrenia The spatiotemporal network dynamics revealing stages susceptible to immune activation Identification of the molecular pathways and regulators in the immune-activated brain
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Affiliation(s)
- Yue Gao
- Center for Genetics and Developmental Systems Biology, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.,Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.,Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence and Guangdong Key Laboratory of Psychiatric Disorders, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.,Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yanjun Li
- Center for Genetics and Developmental Systems Biology, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.,Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence and Guangdong Key Laboratory of Psychiatric Disorders, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.,Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - ShuangYan Li
- Department of Psychiatry, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xiaozhen Liang
- Center for Genetics and Developmental Systems Biology, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zhonglu Ren
- Center for Genetics and Developmental Systems Biology, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xiaoxue Yang
- Center for Genetics and Developmental Systems Biology, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Bin Zhang
- Department of Psychiatry, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yanhui Hu
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Xinping Yang
- Center for Genetics and Developmental Systems Biology, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.,Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence and Guangdong Key Laboratory of Psychiatric Disorders, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.,Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
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30
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Zhang Y, Yao L, Li X, Meng M, Shang Z, Wang Q, Xiao J, Gu X, Xu Z, Zhang X. Schizophrenia risk-gene Crmp2 deficiency causes precocious critical period plasticity and deteriorated binocular vision. Sci Bull (Beijing) 2021; 66:2225-2237. [PMID: 36654114 DOI: 10.1016/j.scib.2021.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 12/15/2020] [Accepted: 01/29/2021] [Indexed: 02/03/2023]
Abstract
Brain-specific loss of a microtubule-binding protein collapsin response mediator protein-2 (CRMP2) in the mouse recapitulates many schizophrenia-like behaviors of human patients, possibly resulting from associated developmental deficits in neuronal differentiation, path-finding, and synapse formation. However, it is still unclear how the Crmp2 loss affects neuronal circuit function and plasticity. By conducting in vivo and ex vivo electrophysiological recording in the mouse primary visual cortex (V1), we reveal that CRMP2 exerts a key regulation on the timing of postnatal critical period (CP) for experience-dependent circuit plasticity of sensory cortex. In the developing V1, the Crmp2 deficiency induces not only a delayed maturation of visual tuning functions but also a precocious CP for visual input-induced ocular dominance plasticity and its induction activity - coincident binocular inputs right after eye-opening. Mechanistically, the Crmp2 deficiency accelerates the maturation process of cortical inhibitory transmission and subsequently promotes an early emergence of balanced excitatory-inhibitory cortical circuits during the postnatal development. Moreover, the precocious CP plasticity results in deteriorated binocular depth perception in adulthood. Thus, these findings suggest that the Crmp2 deficiency dysregulates the timing of CP for experience-dependent refinement of circuit connections and further leads to impaired sensory perception in later life.
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Affiliation(s)
- Yuan Zhang
- State Key Laboratory of Cognitive Neuroscience & Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing 100875, China
| | - Li Yao
- State Key Laboratory of Cognitive Neuroscience & Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing 100875, China
| | - Xiang Li
- State Key Laboratory of Cognitive Neuroscience & Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing 100875, China
| | - Meizhen Meng
- State Key Laboratory of Cognitive Neuroscience & Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing 100875, China
| | - Ziwei Shang
- State Key Laboratory of Cognitive Neuroscience & Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing 100875, China
| | - Qin Wang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Jiaying Xiao
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Xiang Gu
- State Key Laboratory of Cognitive Neuroscience & Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing 100875, China
| | - Zhiheng Xu
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Xiaohui Zhang
- State Key Laboratory of Cognitive Neuroscience & Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing 100875, China.
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Maini K, Hollier JW, Gould H, Bollich V, John LaForge J, Cornett EM, Edinoff AN, Kaye AM, Kaye AD. Lumateperone tosylate, A Selective and Concurrent Modulator of Serotonin, Dopamine, and Glutamate, in the Treatment of Schizophrenia. Health Psychol Res 2021; 9:24932. [PMID: 34746489 DOI: 10.52965/001c.24932] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 06/17/2021] [Indexed: 11/06/2022] Open
Abstract
Purpose of Review This is a comprehensive review of the literature regarding the use of Lumateperone tosylate for schizophrenia. This review presents the background, evidence, and indications for the use of lumateperone tosylate in the treatment of schizophrenia. Recent Findings Schizophrenia is a chronic mental health disorder that affects approximately 3.3 million people in the United States. Its symptoms, which must be present more than six months, are comprised of disorganized behavior and speech, a diminished capacity to comprehend reality, hearing voices unheard by others, seeing things unseen by others, delusions, decreased social commitment, and decreased motivation. The majority of these symptoms can be managed with antipsychotic medication. Lumateperone is a selective and concurrent modulator of serotonin, dopamine, and glutamate, which all mediate or modulate serious mental illness. Summary Schizophrenia is a complex, severe mental illness that affects how the brain processes information. There are many medications used to treat schizophrenia. One antipsychotic agent, lumateperone tosylate, is a newer agent that the FDA recently approved. The most common adverse effects are shown to be mild such as somnolence, constipation, sedation, and fatigue, with the 42 mg recommended dose. Lumateperone tosylate is an FDA-approved drug that can be given only at the 42mg dose once daily with no titration requirements.
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Affiliation(s)
| | | | - Haley Gould
- Louisiana State University Shreveport School of Medicine, Shreveport, LA
| | - Victoria Bollich
- Louisiana State University Shreveport School of Medicine, Shreveport, LA
| | - John John LaForge
- Louisiana State University Shreveport School of Medicine, Shreveport, LA
| | | | | | - Adam M Kaye
- Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA
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Jahn K, Heese A, Kebir O, Groh A, Bleich S, Krebs MO, Frieling H. Differential Methylation Pattern of Schizophrenia Candidate Genes in Tetrahydrocannabinol-Consuming Treatment-Resistant Schizophrenic Patients Compared to Non-Consumer Patients and Healthy Controls. Neuropsychobiology 2021; 80:36-44. [PMID: 32599581 DOI: 10.1159/000507670] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 04/02/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Patients suffering from schizophrenic psychosis show reduced synaptic connectivity compared to healthy individuals. Furthermore, the use of cannabis often precedes the onset of schizophrenic psychosis. Therefore, we investigated whether consumption of cannabis has an impact on the methylation pattern of schizophrenia candidate genes concerned with the development and preservation of synapses and synaptic function. METHODS Fifty blood samples of outpatients affected by treatment-resistant schizophrenic psychosis were collected in the outpatient department of Ch Ste Anne/INSERM (Paris, France). Extracted DNA was sent to the LMN/MHH (Hanover, Germany) where DNA samples were bisulfite converted. The methylation patterns of the promoter region of neuregulin 1 (NRG1), neurexin (NRXN1), disrupted in schizophrenia 1 (DISC1), and microtubule-associated-protein tau (MAPT) were then analysed by sequencing according to Sanger. RESULTS In NRXN1 the group of non-consumer patients showed a methylation rate slightly lower than controls. In patients with preliminary use of tetrahydrocannabinol (THC) the NRXN1 promoter turned out to be methylated almost two times higher than in non-consumer patients. In MAPT, non-consumer patients showed a significant lower mean methylation rate in comparison to controls. In THC-consuming patients the difference compared with controls became less. NRG1 and DISC1 showed no significant differences between groups, whereas DISC1 appeared to be not methylated at all. CONCLUSION In MAPT and NRXN1 mean methylation rates were lower in non-consumer patients compared with controls, which seems to be a compensatory mechanism. With consumption of THC, mean methylation rates were increased: in the case of MAPT compared with controls, and in NRXN1 even significantly beyond that. Methylation of NRG1 and DISC1 seems not to be affected by the psychiatric disorder or by consumption of THC.
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Affiliation(s)
- Kirsten Jahn
- Laboratory for Molecular Neurosciences (LMN), Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover (MHH), Hannover, Germany,
| | - Astrid Heese
- Laboratory for Molecular Neurosciences (LMN), Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover (MHH), Hannover, Germany
| | - Oussama Kebir
- Centre Hospitalier Sainte Anne (Ch Ste Anne), Paris, France
| | - Adrian Groh
- Laboratory for Molecular Neurosciences (LMN), Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover (MHH), Hannover, Germany
| | - Stefan Bleich
- Laboratory for Molecular Neurosciences (LMN), Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover (MHH), Hannover, Germany
| | | | - Helge Frieling
- Laboratory for Molecular Neurosciences (LMN), Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover (MHH), Hannover, Germany
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33
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Jovčevska I, Videtič Paska A. Neuroepigenetics of psychiatric disorders: Focus on lncRNA. Neurochem Int 2021; 149:105140. [PMID: 34298078 DOI: 10.1016/j.neuint.2021.105140] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 07/16/2021] [Accepted: 07/18/2021] [Indexed: 01/01/2023]
Abstract
Understanding the pathology of psychiatric disorders is challenging due to their complexity and multifactorial origin. However, development of high-throughput technologies has allowed for better insight into their molecular signatures. Advancement of sequencing methodologies have made it possible to study not only the protein-coding but also the noncoding genome. It is now clear that besides the genetic component, different epigenetic mechanisms play major roles in the onset and development of psychiatric disorders. Among them, examining the role of long noncoding RNAs (lncRNAs) is a relatively new field. Here, we present an overview of what is currently known about the involvement of lncRNAs in schizophrenia, major depressive and bipolar disorders, as well as suicide. The diagnosis of psychiatric disorders mainly relies on clinical evaluation without using measurable biomarkers. In this regard, lncRNA may open new opportunities for development of molecular tests. However, so far only a small set of known lncRNAs have been characterized at molecular level, which means they have a long way to go before clinical implementation. Understanding how changes in lncRNAs affect the appearance and development of psychiatric disorders may lead to a more classified and objective diagnostic system, but also open up new therapeutic targets for these patients.
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Affiliation(s)
- Ivana Jovčevska
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000, Ljubljana, Slovenia.
| | - Alja Videtič Paska
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000, Ljubljana, Slovenia.
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34
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Rodrigues RS, Paulo SL, Moreira JB, Tanqueiro SR, Sebastião AM, Diógenes MJ, Xapelli S. Adult Neural Stem Cells as Promising Targets in Psychiatric Disorders. Stem Cells Dev 2021; 29:1099-1117. [PMID: 32723008 DOI: 10.1089/scd.2020.0100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The development of new therapies for psychiatric disorders is of utmost importance, given the enormous toll these disorders pose to society nowadays. This should be based on the identification of neural substrates and mechanisms that underlie disease etiopathophysiology. Adult neural stem cells (NSCs) have been emerging as a promising platform to counteract brain damage. In this perspective article, we put forth a detailed view of how NSCs operate in the adult brain and influence brain homeostasis, having profound implications at both behavioral and functional levels. We appraise evidence suggesting that adult NSCs play important roles in regulating several forms of brain plasticity, particularly emotional and cognitive flexibility, and that NSC dynamics are altered upon brain pathology. Furthermore, we discuss the potential therapeutic value of utilizing adult endogenous NSCs as vessels for regeneration, highlighting their importance as targets for the treatment of multiple mental illnesses, such as affective disorders, schizophrenia, and addiction. Finally, we speculate on strategies to surpass current challenges in neuropsychiatric disease modeling and brain repair.
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Affiliation(s)
- Rui S Rodrigues
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.,Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Sara L Paulo
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.,Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - João B Moreira
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.,Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Sara R Tanqueiro
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.,Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Ana M Sebastião
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.,Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Maria J Diógenes
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.,Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Sara Xapelli
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.,Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
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35
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Priya I, Sharma I, Sharma S, Gupta S, Arora M, Bhat GR, Mahajan R, Kapoor N. Genetic association of DISC1 variant rs3738401 with susceptibility to Schizophrenia risk in North Indian population. Meta Gene 2021. [DOI: 10.1016/j.mgene.2021.100923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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36
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Abashkin DA, Kurishev AO, Karpov DS, Golimbet VE. Cellular Models in Schizophrenia Research. Int J Mol Sci 2021; 22:ijms22168518. [PMID: 34445221 PMCID: PMC8395162 DOI: 10.3390/ijms22168518] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/04/2021] [Accepted: 08/05/2021] [Indexed: 12/11/2022] Open
Abstract
Schizophrenia (SZ) is a prevalent functional psychosis characterized by clinical behavioural symptoms and underlying abnormalities in brain function. Genome-wide association studies (GWAS) of schizophrenia have revealed many loci that do not directly identify processes disturbed in the disease. For this reason, the development of cellular models containing SZ-associated variations has become a focus in the post-GWAS research era. The application of revolutionary clustered regularly interspaced palindromic repeats CRISPR/Cas9 gene-editing tools, along with recently developed technologies for cultivating brain organoids in vitro, have opened new perspectives for the construction of these models. In general, cellular models are intended to unravel particular biological phenomena. They can provide the missing link between schizophrenia-related phenotypic features (such as transcriptional dysregulation, oxidative stress and synaptic dysregulation) and data from pathomorphological, electrophysiological and behavioural studies. The objectives of this review are the systematization and classification of cellular models of schizophrenia, based on their complexity and validity for understanding schizophrenia-related phenotypes.
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Affiliation(s)
- Dmitrii A. Abashkin
- Mental Health Research Center, Clinical Genetics Laboratory, Kashirskoe Sh. 34, 115522 Moscow, Russia; (D.A.A.); (A.O.K.); (D.S.K.)
| | - Artemii O. Kurishev
- Mental Health Research Center, Clinical Genetics Laboratory, Kashirskoe Sh. 34, 115522 Moscow, Russia; (D.A.A.); (A.O.K.); (D.S.K.)
| | - Dmitry S. Karpov
- Mental Health Research Center, Clinical Genetics Laboratory, Kashirskoe Sh. 34, 115522 Moscow, Russia; (D.A.A.); (A.O.K.); (D.S.K.)
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Str. 32, 119991 Moscow, Russia
| | - Vera E. Golimbet
- Mental Health Research Center, Clinical Genetics Laboratory, Kashirskoe Sh. 34, 115522 Moscow, Russia; (D.A.A.); (A.O.K.); (D.S.K.)
- Correspondence:
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37
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Hidden Role of Gut Microbiome Dysbiosis in Schizophrenia: Antipsychotics or Psychobiotics as Therapeutics? Int J Mol Sci 2021; 22:ijms22147671. [PMID: 34299291 PMCID: PMC8307070 DOI: 10.3390/ijms22147671] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/14/2021] [Accepted: 07/15/2021] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia is a chronic, heterogeneous neurodevelopmental disorder that has complex symptoms and uncertain etiology. Mounting evidence indicates the involvement of genetics and epigenetic disturbances, alteration in gut microbiome, immune system abnormalities, and environmental influence in the disease, but a single root cause and mechanism involved has yet to be conclusively determined. Consequently, the identification of diagnostic markers and the development of psychotic drugs for the treatment of schizophrenia faces a high failure rate. This article surveys the etiology of schizophrenia with a particular focus on gut microbiota regulation and the microbial signaling system that correlates with the brain through the vagus nerve, enteric nervous system, immune system, and production of postbiotics. Gut microbially produced molecules may lay the groundwork for further investigations into the role of gut microbiota dysbiosis and the pathophysiology of schizophrenia. Current treatment of schizophrenia is limited to psychotherapy and antipsychotic drugs that have significant side effects. Therefore, alternative therapeutic options merit exploration. The use of psychobiotics alone or in combination with antipsychotics may promote the development of novel therapeutic strategies. In view of the individual gut microbiome structure and personalized response to antipsychotic drugs, a tailored and targeted manipulation of gut microbial diversity naturally by novel prebiotics (non-digestible fiber) may be a successful alternative therapeutic for the treatment of schizophrenia patients.
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38
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Munawar N, Ahsan K, Muhammad K, Ahmad A, Anwar MA, Shah I, Al Ameri AK, Al Mughairbi F. Hidden Role of Gut Microbiome Dysbiosis in Schizophrenia: Antipsychotics or Psychobiotics as Therapeutics? Int J Mol Sci 2021. [DOI: https://doi.org/10.3390/ijms22147671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Schizophrenia is a chronic, heterogeneous neurodevelopmental disorder that has complex symptoms and uncertain etiology. Mounting evidence indicates the involvement of genetics and epigenetic disturbances, alteration in gut microbiome, immune system abnormalities, and environmental influence in the disease, but a single root cause and mechanism involved has yet to be conclusively determined. Consequently, the identification of diagnostic markers and the development of psychotic drugs for the treatment of schizophrenia faces a high failure rate. This article surveys the etiology of schizophrenia with a particular focus on gut microbiota regulation and the microbial signaling system that correlates with the brain through the vagus nerve, enteric nervous system, immune system, and production of postbiotics. Gut microbially produced molecules may lay the groundwork for further investigations into the role of gut microbiota dysbiosis and the pathophysiology of schizophrenia. Current treatment of schizophrenia is limited to psychotherapy and antipsychotic drugs that have significant side effects. Therefore, alternative therapeutic options merit exploration. The use of psychobiotics alone or in combination with antipsychotics may promote the development of novel therapeutic strategies. In view of the individual gut microbiome structure and personalized response to antipsychotic drugs, a tailored and targeted manipulation of gut microbial diversity naturally by novel prebiotics (non-digestible fiber) may be a successful alternative therapeutic for the treatment of schizophrenia patients.
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Ohnishi T, Kiyama Y, Arima‐Yoshida F, Kadota M, Ichikawa T, Yamada K, Watanabe A, Ohba H, Tanaka K, Nakaya A, Horiuchi Y, Iwayama Y, Toyoshima M, Ogawa I, Shimamoto‐Mitsuyama C, Maekawa M, Balan S, Arai M, Miyashita M, Toriumi K, Nozaki Y, Kurokawa R, Suzuki K, Yoshikawa A, Toyota T, Hosoya T, Okuno H, Bito H, Itokawa M, Kuraku S, Manabe T, Yoshikawa T. Cooperation of LIM domain-binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia. EMBO Mol Med 2021; 13:e12574. [PMID: 33656268 PMCID: PMC8033514 DOI: 10.15252/emmm.202012574] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 01/21/2021] [Accepted: 01/25/2021] [Indexed: 01/15/2023] Open
Abstract
Genomic defects with large effect size can help elucidate unknown pathologic architecture of mental disorders. We previously reported on a patient with schizophrenia and a balanced translocation between chromosomes 4 and 13 and found that the breakpoint within chromosome 4 is located near the LDB2 gene. We show here that Ldb2 knockout (KO) mice displayed multiple deficits relevant to mental disorders. In particular, Ldb2 KO mice exhibited deficits in the fear-conditioning paradigm. Analysis of the amygdala suggested that dysregulation of synaptic activities controlled by the immediate early gene Arc is involved in the phenotypes. We show that LDB2 forms protein complexes with known transcription factors. Consistently, ChIP-seq analyses indicated that LDB2 binds to > 10,000 genomic sites in human neurospheres. We found that many of those sites, including the promoter region of ARC, are occupied by EGR transcription factors. Our previous study showed an association of the EGR family genes with schizophrenia. Collectively, the findings suggest that dysregulation in the gene expression controlled by the LDB2-EGR axis underlies a pathogenesis of subset of mental disorders.
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40
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Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness. Transl Psychiatry 2021; 11:135. [PMID: 33608504 PMCID: PMC7895946 DOI: 10.1038/s41398-021-01256-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 11/24/2020] [Accepted: 01/22/2021] [Indexed: 12/17/2022] Open
Abstract
A balanced t(1;11) translocation that directly disrupts DISC1 is linked to schizophrenia and affective disorders. We previously showed that a mutant mouse, named Der1, recapitulates the effect of the translocation upon DISC1 expression. Here, RNAseq analysis of Der1 mouse brain tissue found enrichment for dysregulation of the same genes and molecular pathways as in neuron cultures generated previously from human t(1;11) translocation carriers via the induced pluripotent stem cell route. DISC1 disruption therefore apparently accounts for a substantial proportion of the effects of the t(1;11) translocation. RNAseq and pathway analysis of the mutant mouse predicts multiple Der1-induced alterations converging upon synapse function and plasticity. Synaptosome proteomics confirmed that the Der1 mutation impacts synapse composition, and electrophysiology found reduced AMPA:NMDA ratio in hippocampal neurons, indicating changed excitatory signalling. Moreover, hippocampal parvalbumin-positive interneuron density is increased, suggesting that the Der1 mutation affects inhibitory control of neuronal circuits. These phenotypes predict that neurotransmission is impacted at many levels by DISC1 disruption in human t(1;11) translocation carriers. Notably, genes implicated in schizophrenia, depression and bipolar disorder by large-scale genetic studies are enriched among the Der1-dysregulated genes, just as we previously observed for the t(1;11) translocation carrier-derived neurons. Furthermore, RNAseq analysis predicts that the Der1 mutation primarily targets a subset of cell types, pyramidal neurons and interneurons, previously shown to be vulnerable to the effects of common schizophrenia-associated genetic variants. In conclusion, DISC1 disruption by the t(1;11) translocation may contribute to the psychiatric disorders of translocation carriers through commonly affected pathways and processes in neurotransmission.
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41
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García-González J, de Quadros B, Havelange W, Brock AJ, Brennan CH. Behavioral Effects of Developmental Exposure to JWH-018 in Wild-Type and Disrupted in Schizophrenia 1 ( disc1) Mutant Zebrafish. Biomolecules 2021; 11:biom11020319. [PMID: 33669793 PMCID: PMC7922669 DOI: 10.3390/biom11020319] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/15/2021] [Accepted: 02/16/2021] [Indexed: 11/17/2022] Open
Abstract
Synthetic cannabinoids can cause acute adverse psychological effects, but the potential impact when exposure happens before birth is unknown. Use of synthetic cannabinoids during pregnancy may affect fetal brain development, and such effects could be moderated by the genetic makeup of an individual. Disrupted in schizophrenia 1 (DISC1) is a gene with important roles in neurodevelopment that has been associated with psychiatric disorders in pedigree analyses. Using zebrafish as a model, we investigated (1) the behavioral impact of developmental exposure to 3 μM 1-pentyl-3-(1-naphthoyl)-indole (JWH-018; a common psychoactive synthetic cannabinoid) and (2) whether disc1 moderates the effects of JWH-018. As altered anxiety responses are seen in several psychiatric disorders, we focused on zebrafish anxiety-like behavior. Zebrafish embryos were exposed to JWH-018 from one to six days post-fertilization. Anxiety-like behavior was assessed using forced light/dark and acoustic startle assays in larvae and novel tank diving in adults. Compared to controls, both acutely and developmentally exposed zebrafish larvae had impaired locomotion during the forced light/dark test, but anxiety levels and response to startle stimuli were unaltered. Adult zebrafish developmentally exposed to JWH-018 spent less time on the bottom of the tank, suggesting decreased anxiety. Loss-of-function in disc1 increased anxiety-like behavior in the tank diving assay but did not alter sensitivity to JWH-018. Results suggest developmental exposure to JWH-018 has a long-term behavioral impact in zebrafish, which is not moderated by disc1.
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Affiliation(s)
- Judit García-González
- School of Biological and Chemical Sciences, Queen Mary, University of London, London E1 4NS, UK; (J.G.-G.); (B.d.Q.); (W.H.)
| | - Bruno de Quadros
- School of Biological and Chemical Sciences, Queen Mary, University of London, London E1 4NS, UK; (J.G.-G.); (B.d.Q.); (W.H.)
| | - William Havelange
- School of Biological and Chemical Sciences, Queen Mary, University of London, London E1 4NS, UK; (J.G.-G.); (B.d.Q.); (W.H.)
| | | | - Caroline H. Brennan
- School of Biological and Chemical Sciences, Queen Mary, University of London, London E1 4NS, UK; (J.G.-G.); (B.d.Q.); (W.H.)
- Correspondence:
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Stone W, Nunes A, Akiyama K, Akula N, Ardau R, Aubry JM, Backlund L, Bauer M, Bellivier F, Cervantes P, Chen HC, Chillotti C, Cruceanu C, Dayer A, Degenhardt F, Del Zompo M, Forstner AJ, Frye M, Fullerton JM, Grigoroiu-Serbanescu M, Grof P, Hashimoto R, Hou L, Jiménez E, Kato T, Kelsoe J, Kittel-Schneider S, Kuo PH, Kusumi I, Lavebratt C, Manchia M, Martinsson L, Mattheisen M, McMahon FJ, Millischer V, Mitchell PB, Nöthen MM, O'Donovan C, Ozaki N, Pisanu C, Reif A, Rietschel M, Rouleau G, Rybakowski J, Schalling M, Schofield PR, Schulze TG, Severino G, Squassina A, Veeh J, Vieta E, Trappenberg T, Alda M. Prediction of lithium response using genomic data. Sci Rep 2021; 11:1155. [PMID: 33441847 PMCID: PMC7806976 DOI: 10.1038/s41598-020-80814-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 12/18/2020] [Indexed: 12/23/2022] Open
Abstract
Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen’s kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [− 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.
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Affiliation(s)
- William Stone
- Faculty of Computer Science, Dalhousie University, Halifax, NS, Canada
| | - Abraham Nunes
- Faculty of Computer Science, Dalhousie University, Halifax, NS, Canada.,Department of Psychiatry, Dalhousie University, Halifax, NS, Canada
| | - Kazufumi Akiyama
- Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
| | | | - Raffaella Ardau
- Unit of Clinical Pharmacology, University Hospital of Cagliari, Cagliari, Italy
| | - Jean-Michel Aubry
- Department of Psychiatry, University of Geneva, Geneva, Switzerland.,Department of Psychiatry, University of Geneva Hospitals, Geneva, Switzerland
| | - Lena Backlund
- Department of Clinical Neuroscience, the Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.,Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden
| | - Michael Bauer
- Department of Psychiatry and Psychotherapy, Medical Faculty, Technische Universität Berlin, Dresden, Germany
| | - Frank Bellivier
- Université Paris Diderot, Paris, France.,Inserm, U1144, Team 1, Paris, France
| | - Pablo Cervantes
- Department of Psychiatry, McGill University, Montreal, Canada
| | - Hsi-Chung Chen
- Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan
| | - Caterina Chillotti
- Unit of Clinical Pharmacology, University Hospital of Cagliari, Cagliari, Italy
| | - Cristiana Cruceanu
- Department of Translational Research, Max Planck Institute of Psychiatry, Munich, Germany
| | - Alexandre Dayer
- Department of Psychiatry, University of Geneva, Geneva, Switzerland.,Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland
| | - Franziska Degenhardt
- Institute of Human Genetics, School of Medicine, University Hospital Bonn, University of Bonn, Bonn, Germany.,Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, Essen, Germany
| | - Maria Del Zompo
- Unit of Clinical Pharmacology, University Hospital of Cagliari, Cagliari, Italy.,Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Andreas J Forstner
- Institute of Human Genetics, School of Medicine, University Hospital Bonn, University of Bonn, Bonn, Germany.,Centre for Human Genetics, University of Marburg, Marburg, Germany
| | - Mark Frye
- Department of Psychiatry, Mayo Clinic, Rochester, USA
| | | | - Maria Grigoroiu-Serbanescu
- Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania
| | - Paul Grof
- Mood Disorders Center Ottawa, Ottawa, Canada
| | - Ryota Hashimoto
- Department of Pathology of Mental Diseases, National Institute of Mental Health, Tokyo, Japan.,Department of Psychiatry, Osaka University, Osaka, Japan
| | - Liping Hou
- National Institute of Mental Health, Bethesda, USA
| | - Esther Jiménez
- Hospital Clinic, University of Barcelona, Barcelona, Spain.,Institut d'Investigacio Biomedica August Pi i Sunyer, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain
| | - Tadafumi Kato
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako, Japan
| | - John Kelsoe
- Department of Psychiatry, UCSD, San Diego, CA, USA
| | - Sarah Kittel-Schneider
- Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital of Frankfurt, Frankfurt am Main, Germany.,Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany
| | - Po-Hsiu Kuo
- Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.,Department of Public Health, National Taiwan University, Taipei, Taiwan
| | - Ichiro Kusumi
- Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Catharina Lavebratt
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden
| | - Mirko Manchia
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.,Department of Pharmacology, Dalhousie University, Halifax, NS, Canada
| | - Lina Martinsson
- Department of Clinical Neuroscience, the Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden
| | | | | | - Vincent Millischer
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden
| | - Philip B Mitchell
- School of Psychiatry, University of New South Wales, Sydney, Australia
| | - Markus M Nöthen
- Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Claire O'Donovan
- Department of Psychiatry, Dalhousie University, Halifax, NS, Canada
| | - Norio Ozaki
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Claudia Pisanu
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Andreas Reif
- Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital of Frankfurt, Frankfurt am Main, Germany
| | - Marcella Rietschel
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Guy Rouleau
- Montreal Neurological Institute, McGill University, Montreal, Canada
| | - Janusz Rybakowski
- Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland
| | - Martin Schalling
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden
| | - Peter R Schofield
- School of Psychiatry, University of New South Wales, Sydney, Australia
| | - Thomas G Schulze
- Institute of Psychiatric Phenomics and Genomics, University of Munich, Munich, Germany
| | - Giovanni Severino
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Alessio Squassina
- Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.,Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Julia Veeh
- Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital of Frankfurt, Frankfurt am Main, Germany
| | - Eduard Vieta
- Hospital Clinic, University of Barcelona, Barcelona, Spain.,Institut d'Investigacio Biomedica August Pi i Sunyer, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain
| | | | - Martin Alda
- Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
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Willner MJ, Xiao Y, Kim HS, Chen X, Xu B, Leong KW. Modeling SARS-CoV-2 infection in individuals with opioid use disorder with brain organoids. J Tissue Eng 2021; 12:2041731420985299. [PMID: 33738089 PMCID: PMC7934045 DOI: 10.1177/2041731420985299] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 12/13/2020] [Indexed: 01/10/2023] Open
Abstract
The COVID-19 pandemic has aggravated a preexisting epidemic: the opioid crisis. Much literature has shown that the circumstances imposed by COVID-19, such as social distancing regulations, medical and financial instability, and increased mental health issues, have been detrimental to those with opioid use disorder (OUD). In addition, unexpected neurological sequelae in COVID-19 patients suggest that COVID-19 compromises neuroimmunity, induces hypoxia, and causes respiratory depression, provoking similar effects as those caused by opioid exposure. Combined conditions of COVID-19 and OUD could lead to exacerbated complications. With limited human in vivo options to study these complications, we suggest that iPSC-derived brain organoid models may serve as a useful platform to investigate the physiological connection between COVID-19 and OUD. This mini-review highlights the advances of brain organoids in other neuropsychiatric and infectious diseases and suggests their potential utility for investigating OUD and COVID-19, respectively.
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Affiliation(s)
- Moshe J Willner
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Yang Xiao
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Hye Sung Kim
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
- Institute of Tissue Regeneration Engineering, Dankook University, Cheonan, Republic of Korea
- Department of Regenerative Dental Medicine, College of Dentistry, Dankook University, Cheonan, Republic of Korea
- Cell & Matter Institute, Dankook University, Cheonan, Republic of Korea
| | - Xuejing Chen
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
- Department of Physics, Tsinghua University, Beijing, China
| | - Bin Xu
- Department of Psychiatry, Columbia University Medical Center, New York, NY, USA
| | - Kam W Leong
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA
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Venkatesan D, Iyer M, Narayanasamy A, Siva K, Vellingiri B. Kynurenine pathway in Parkinson's disease-An update. eNeurologicalSci 2020; 21:100270. [PMID: 33134567 PMCID: PMC7585940 DOI: 10.1016/j.ensci.2020.100270] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/05/2020] [Accepted: 08/26/2020] [Indexed: 12/24/2022] Open
Abstract
Parkinson's disease (PD) is a complex multi-factorial neurodegenerative disorder where various altered metabolic pathways contribute to the progression of the disease. Tryptophan (TRP) is a major precursor in kynurenine pathway (KP) and it has been discussed in various in vitro studies that the metabolites quinolinic acid (QUIN) causes neurotoxicity and kynurenic acid (KYNA) acts as neuroprotectant respectively. More studies are also focused on the effects of other KP metabolites and its enzymes as it has an association with ageing and PD pathogenesis. Until now, very few studies have targeted the role of genetic mutations in abnormal KP metabolism in adverse conditions of PD. Therefore, the present review gives an updated research studies on KP in connection with PD. Moreover, the review emphasizes on the urge for the development of biomarkers and also this would be an initiative in generating an alternative therapeutic approach for PD.
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Key Words
- 3-HAA, 3-hydroxyanthranilic acid
- 3-HK, 3-hydroxykynurenine
- 6-OHDA, 6-hydroxydopamine
- AA, anthranilic acid
- ACMSD, amino-carboxymuconatesemialdehyde decarboxylase
- AD, Alzheimer's disease
- ATP, adenosine triphosphate
- Ageing
- AhR, aryl hydrocarbon receptor
- Biomarkers
- CNS, central nervous system
- CSF, cerebrospinal fluid
- DA, dopaminergic
- FAM, formamidase
- IDO-1, indoleamine-2,3-dioxygenases
- IFN-γ, interferon-γ
- KATs, kynurenine aminotransferases
- KMO, kynurenine −3-monooxygenase
- KP, Kynurenine pathway
- KYN, kynurenine
- KYNA, kynurenic acid
- Kynurenine pathway (KP)
- L-DOPA, L-dopamine
- LID, L-DOPA-induced dyskinesia
- MPTP, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine
- NAD+, nicotinamide adenine dinucleotide
- NADPH, nicotinamide adenine dinucleotide phosphate
- NFK, N′-formylkynurenine
- NMDA, N-methyl-d-aspartate
- PA, picolinic acid
- PD, Parkinson's disease
- Parkinson's disease (PD)
- QUIN, quinolinic acid
- RBCs, red blood cells
- SNpc, substantianigra pars compacta
- TDO, tryptophan 2,3-dioxygenase
- TRP, tryptophan
- Therapeutics
- XA, xanthurenic acid
- ZNS, zonisamide
- α-synuclein, αSyn
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Affiliation(s)
- Dhivya Venkatesan
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India
| | - Mahalaxmi Iyer
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore 641 043, Tamil Nadu, India
| | - Arul Narayanasamy
- Disease Proteomics Laboratory, Department of Zoology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India
| | - Kamalakannan Siva
- National Centre for Disease Control, Ministry of Health and Family Welfare, Government of India, New Delhi 110054, India
| | - Balachandar Vellingiri
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India
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45
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Aznaourova M, Schmerer N, Schmeck B, Schulte LN. Disease-Causing Mutations and Rearrangements in Long Non-coding RNA Gene Loci. Front Genet 2020; 11:527484. [PMID: 33329688 PMCID: PMC7735109 DOI: 10.3389/fgene.2020.527484] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 11/02/2020] [Indexed: 12/12/2022] Open
Abstract
The classic understanding of molecular disease-mechanisms is largely based on protein-centric models. During the past decade however, genetic studies have identified numerous disease-loci in the human genome that do not encode proteins. Such non-coding DNA variants increasingly gain attention in diagnostics and personalized medicine. Of particular interest are long non-coding RNA (lncRNA) genes, which generate transcripts longer than 200 nucleotides that are not translated into proteins. While most of the estimated ~20,000 lncRNAs currently remain of unknown function, a growing number of genetic studies link lncRNA gene aberrations with the development of human diseases, including diabetes, AIDS, inflammatory bowel disease, or cancer. This suggests that the protein-centric view of human diseases does not capture the full complexity of molecular patho-mechanisms, with important consequences for molecular diagnostics and therapy. This review illustrates well-documented lncRNA gene aberrations causatively linked to human diseases and discusses potential lessons for molecular disease models, diagnostics, and therapy.
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Affiliation(s)
- Marina Aznaourova
- Institute for Lung Research, Philipps University Marburg, Marburg, Germany
| | - Nils Schmerer
- Institute for Lung Research, Philipps University Marburg, Marburg, Germany
| | - Bernd Schmeck
- Institute for Lung Research, Philipps University Marburg, Marburg, Germany.,Systems Biology Platform, German Center for Lung Research (DZL), Philipps University Marburg, Marburg, Germany.,Center for Synthetic Microbiology (SYNMIKRO), Philipps University Marburg, Marburg, Germany
| | - Leon N Schulte
- Institute for Lung Research, Philipps University Marburg, Marburg, Germany.,Systems Biology Platform, German Center for Lung Research (DZL), Philipps University Marburg, Marburg, Germany
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46
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Horiuchi Y, Ichikawa T, Ohnishi T, Iwayama Y, Toriumi K, Miyashita M, Nohara I, Obata N, Toyota T, Yoshikawa T, Itokawa M, Arai M. LDB2 locus disruption on 4p16.1 as a risk factor for schizophrenia and bipolar disorder. Hum Genome Var 2020; 7:31. [PMID: 33082982 PMCID: PMC7524746 DOI: 10.1038/s41439-020-00117-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 07/27/2020] [Accepted: 08/17/2020] [Indexed: 01/15/2023] Open
Abstract
We had previously reported the case of a male patient with schizophrenia, having de-novo balanced translocation. Here, we determined the exact breakpoints in chromosomes 4 and 13. The breakpoint within chromosome 4 was mapped to a region 32.6 kbp upstream of the LDB2 gene encoding Lim domain binding 2. Variant screening in LDB2 revealed a rare novel missense variant in patients with psychiatric disorder.
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Affiliation(s)
- Yasue Horiuchi
- Schizophrenia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Tomoe Ichikawa
- Schizophrenia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
- Department of Infection Control Science, Meiji Pharmaceutical University, Tokyo, Japan
| | - Tetsuo Ohnishi
- Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama Japan
| | - Yoshimi Iwayama
- Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama Japan
| | - Kazuya Toriumi
- Schizophrenia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Mitsuhiro Miyashita
- Schizophrenia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Izumi Nohara
- Schizophrenia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Nanako Obata
- Schizophrenia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Tomoko Toyota
- Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama Japan
| | - Takeo Yoshikawa
- Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama Japan
| | - Masanari Itokawa
- Schizophrenia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Makoto Arai
- Schizophrenia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
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47
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Modeling Brain Disorders Using Induced Pluripotent Stem Cells. Cold Spring Harb Perspect Biol 2020; 12:cshperspect.a035659. [PMID: 31767646 DOI: 10.1101/cshperspect.a035659] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Brain disorders, from neurodegenerative to psychiatric disorders, are among the most challenging conditions to study because of the intricate nature of the human brain and the limitations of existing model systems in recapitulating all these intricacies. However, innovations in stem cell technologies now allow us to reprogram patient somatic cells to induced pluripotent stem cells (iPSCs), which can then be differentiated to disease-relevant neural and glial cells. iPSCs are a valuable tool to model brain disorders, as they can be derived from patients with known symptom histories, genetics, and drug-response profiles. Here, we discuss the premise and validity of the iPSC-based in vitro model system and highlight key findings from the most commonly studied neurodegenerative and psychiatric disorders.
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48
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Tibbo AJ, Baillie GS. Phosphodiesterase 4B: Master Regulator of Brain Signaling. Cells 2020; 9:cells9051254. [PMID: 32438615 PMCID: PMC7291338 DOI: 10.3390/cells9051254] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 05/13/2020] [Accepted: 05/14/2020] [Indexed: 12/25/2022] Open
Abstract
Phosphodiesterases (PDEs) are the only superfamily of enzymes that have the ability to break down cyclic nucleotides and, as such, they have a pivotal role in neurological disease and brain development. PDEs have a modular structure that allows targeting of individual isoforms to discrete brain locations and it is often the location of a PDE that shapes its cellular function. Many of the eleven different families of PDEs have been associated with specific diseases. However, we evaluate the evidence, which suggests the activity from a sub-family of the PDE4 family, namely PDE4B, underpins a range of important functions in the brain that positions the PDE4B enzymes as a therapeutic target for a diverse collection of indications, such as, schizophrenia, neuroinflammation, and cognitive function.
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49
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Sultana R, Lee CC. Expression of Behavioral Phenotypes in Genetic and Environmental Mouse Models of Schizophrenia. Front Behav Neurosci 2020; 14:29. [PMID: 32184711 PMCID: PMC7058961 DOI: 10.3389/fnbeh.2020.00029] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 02/07/2020] [Indexed: 02/04/2023] Open
Abstract
Schizophrenia is a neuropsychiatric disorder characterized by multifactorial etiology involving complex interactions among genetic and environmental factors. "Multiple-hit" models of the disorder can explain its variable incidence and prevalence in related individuals. Hence, there is a dire need to understand these interactions in the emergence of schizophrenia. To test these factors in the emergence of schizophrenia-like behaviors, we employed a genetic mouse model of the disorder (harboring the DISC1 mutation) along with various environmental insults, such as early life stress (maternal separation of pups) and/or pharmacological interventions (ketamine injections). When assessed on a battery of behavioral tests, we found that environmental interventions affect the severity of behavioral phenotypes in terms of increased negative behavior, as shown by reduced mobility in the forced swim and tail suspension tests, and changes to positive and cognitive symptoms, such as increased locomotion and disrupted PPI along with reduced working memory, respectively. Among the various interventions, the genetic mutation had the most profound effect on behavioral aberrations, followed by an environmental intervention by ketamine injections and ketamine-injected animals that were maternally separated during early postnatal days. We conclude that although environmental factors increased the prevalence of aberrant behavioral phenotypes, genetic background is still the predominant influence on phenotypic alterations in these mouse models of schizophrenia.
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Affiliation(s)
- Razia Sultana
- Neural Systems Laboratory, Department of Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA, United States
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50
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Tang W, Davidson JD, Zhang G, Conen KE, Fang J, Serluca F, Li J, Xiong X, Coble M, Tsai T, Molind G, Fawcett CH, Sanchez E, Zhu P, Couzin ID, Fishman MC. Genetic Control of Collective Behavior in Zebrafish. iScience 2020; 23:100942. [PMID: 32179471 PMCID: PMC7068127 DOI: 10.1016/j.isci.2020.100942] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 01/17/2020] [Accepted: 02/21/2020] [Indexed: 01/02/2023] Open
Abstract
Many animals, including humans, have evolved to live and move in groups. In humans, disrupted social interactions are a fundamental feature of many psychiatric disorders. However, we know little about how genes regulate social behavior. Zebrafish may serve as a powerful model to explore this question. By comparing the behavior of wild-type fish with 90 mutant lines, we show that mutations of genes associated with human psychiatric disorders can alter the collective behavior of adult zebrafish. We identify three categories of behavioral variation across mutants: "scattered," in which fish show reduced cohesion; "coordinated," in which fish swim more in aligned schools; and "huddled," in which fish form dense but disordered groups. Changes in individual interaction rules can explain these differences. This work demonstrates how emergent patterns in animal groups can be altered by genetic changes in individuals and establishes a framework for understanding the fundamentals of social information processing.
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Affiliation(s)
- Wenlong Tang
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Jacob D Davidson
- Department of Collective Behavior, Max Planck Institute of Animal Behavior, Universitätstraße 10, 78764 Konstanz, Germany; Centre for the Advanced Study of Collective Behavior, University of Konstanz, Universitätstraße 10, 78764 Konstanz, Germany; Department of Biology, University of Konstanz, Universitätstraße 10, 78764 Konstanz, Germany
| | - Guoqiang Zhang
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Katherine E Conen
- Department of Collective Behavior, Max Planck Institute of Animal Behavior, Universitätstraße 10, 78764 Konstanz, Germany; Centre for the Advanced Study of Collective Behavior, University of Konstanz, Universitätstraße 10, 78764 Konstanz, Germany; Department of Biology, University of Konstanz, Universitätstraße 10, 78764 Konstanz, Germany
| | - Jian Fang
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Fabrizio Serluca
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Jingyao Li
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Xiaorui Xiong
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Matthew Coble
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Tingwei Tsai
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Gregory Molind
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Caroline H Fawcett
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Ellen Sanchez
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Peixin Zhu
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Iain D Couzin
- Department of Collective Behavior, Max Planck Institute of Animal Behavior, Universitätstraße 10, 78764 Konstanz, Germany; Centre for the Advanced Study of Collective Behavior, University of Konstanz, Universitätstraße 10, 78764 Konstanz, Germany; Department of Biology, University of Konstanz, Universitätstraße 10, 78764 Konstanz, Germany.
| | - Mark C Fishman
- Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA.
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