|
1
|
Longhena F, Faustini G, Brembati V, Pizzi M, Benfenati F, Bellucci A. An updated reappraisal of synapsins: structure, function and role in neurological and psychiatric disorders. Neurosci Biobehav Rev 2021; 130:33-60. [PMID: 34407457 DOI: 10.1016/j.neubiorev.2021.08.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 07/29/2021] [Accepted: 08/09/2021] [Indexed: 01/02/2023]
Abstract
Synapsins (Syns) are phosphoproteins strongly involved in neuronal development and neurotransmitter release. Three distinct genes SYN1, SYN2 and SYN3, with elevated evolutionary conservation, have been described to encode for Synapsin I, Synapsin II and Synapsin III, respectively. Syns display a series of common features, but also exhibit distinctive localization, expression pattern, post-translational modifications (PTM). These characteristics enable their interaction with other synaptic proteins, membranes and cytoskeletal components, which is essential for the proper execution of their multiple functions in neuronal cells. These include the control of synapse formation and growth, neuron maturation and renewal, as well as synaptic vesicle mobilization, docking, fusion, recycling. Perturbations in the balanced expression of Syns, alterations of their PTM, mutations and polymorphisms of their encoding genes induce severe dysregulations in brain networks functions leading to the onset of psychiatric or neurological disorders. This review presents what we have learned since the discovery of Syn I in 1977, providing the state of the art on Syns structure, function, physiology and involvement in central nervous system disorders.
Collapse
Affiliation(s)
- Francesca Longhena
- Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
| | - Gaia Faustini
- Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
| | - Viviana Brembati
- Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
| | - Marina Pizzi
- Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
| | - Fabio Benfenati
- Italian Institute of Technology, Via Morego 30, Genova, Italy; IRCSS Policlinico San Martino Hospital, Largo Rosanna Benzi 10, 16132, Genova, Italy.
| | - Arianna Bellucci
- Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy; Laboratory for Preventive and Personalized Medicine, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
| |
Collapse
|
|
2
|
Dysfunction of the serotonergic system in the brain of synapsin triple knockout mice is associated with behavioral abnormalities resembling synapsin-related human pathologies. Prog Neuropsychopharmacol Biol Psychiatry 2021; 105:110135. [PMID: 33058959 DOI: 10.1016/j.pnpbp.2020.110135] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/31/2020] [Accepted: 10/06/2020] [Indexed: 11/23/2022]
Abstract
Synapsins (Syns) are a family of phosphoproteins associated with synaptic vesicles (SVs). Their main function is to regulate neurotransmitter release by maintaining a reserve pool of SVs at the presynaptic terminal. Previous studies reported that the deletion of one or more Syn genes in mice results in an epileptic phenotype and autism-related behavioral abnormalities. Here we aimed at characterizing the behavioral phenotype and neurobiological correlates of the deletion of Syns in a Syn triple knockout (TKO) mouse model. Wild type (WT) and TKO mice were tested in the open field, novelty suppressed feeding, light-dark box, forced swim, tail suspension and three-chamber sociability tests. Using in vivo electrophysiology, we recorded the spontaneous activity of dorsal raphe nucleus (DRN) serotonin (5-HT) and ventral tegmental area (VTA) dopamine (DA) neurons. Levels of 5-HT and DA in the frontal cortex and hippocampus of WT and TKO mice were also assessed using a High-Performance Liquid Chromatography. TKO mice displayed hyperactivity and impaired social and anxiety-like behavior. Behavioral dysfunctions were accompanied by reduced firing activity of DRN 5-HT, but not VTA DA, neurons. TKO mice also showed increased responsiveness of DRN 5-HT-1A autoreceptors, measured as a reduced dose of the 5-HT-1A agonist 8-OH-DPAT necessary to inhibit DRN 5-HT firing activity by 50%. Finally, hippocampal 5-HT levels were lower in TKO than in WT mice. Overall, Syns deletion in mice leads to a reduction in DRN 5-HT firing activity and hippocampal 5-HT levels along with behavioral alterations reminiscent of human neuropsychiatric conditions associated with Syn dysfunction.
Collapse
|
|
3
|
Quintas M, Neto JL, Sequeiros J, Sousa A, Pereira-Monteiro J, Lemos C, Alonso I. Going Deep into Synaptic Vesicle Machinery Genes and Migraine Susceptibility - A Case-Control Association Study. Headache 2020; 60:2152-2165. [PMID: 32979221 DOI: 10.1111/head.13957] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 08/28/2020] [Accepted: 08/29/2020] [Indexed: 11/29/2022]
Abstract
OBJECTIVE A number of observations, including among our study population, have implicated variants in the syntaxin-1A, a component of the synaptic vesicles, in migraine susceptibility. Therefore, we hypothesize that variants in other components of the vesicle machinery are involved in migraine. BACKGROUND Migraine is a common and complex neurologic disorder that affects approximately 15-18% of the general population. The exact cause of migraine is unknown; however, genetic studies have made possible substantial progress toward the identification of underlying molecular pathways. Neurotransmitters have been for long considered to have a key role in migraine pathophysiology; so we investigated common variants in genes involved in the synaptic vesicle machinery and their impact in migraine susceptibility. METHODS We performed a case-control study comprising 188 unrelated patients with headache and 286 healthy controls in a population from the north of Portugal. Benefiting from the presence of linkage disequilibrium, we selected and genotyped 119 tagging single-nucleotide polymorphisms in 18 genes. RESULTS We found significant associations between single-nucleotide variants and migraine in 7 genes, SYN1, SYN2, SNAP25, VAMP2, STXBP1, STXBP5, and UNC13A, either conferring an increased risk or protection of migraine. Due to SYN1 X-chromosomal location, we performed the statistical analysis separated by gender and, in the female group, the C allele of rs5906435 increased the risk for migraine susceptibility (P = .021; OR = 1.69; 95% CI: 1.21-2.34). In contrast, the TT genotype of the same variant emerged as a potential protective factor (P = .003; OR = 0.45; 95% CI: 0.27-0.74). The SYN2 analysis supported the rs3773364's G allele (P = .014) as a risk factor for migraine, and although not statistically significant after correction, the AG genotype (P = .006; OR = 1.86; 95% CI: 1.20-2.90) reinforced the allelic findings. Additionally, we found the SNAP25-rs363039's CT genotype (P = .001; OR = 2.14; 95% CI: 1.36-3.34), the STXBP5-rs1765028's T allele (P = .041; OR = 1.46; 95% CI: 1.13-1.90), and the UNC13B-rs7851161's TT genotype (P = .001; OR = 2.14; 95% CI: 1.36-3.34) as statistically significant risk factors for migraine liability. VAMP2-rs1150's G allele revealed a risk association to migraine, not statistically significant after correction (P = .068). Additionally, we found haplotypes in SYN1, SYN2, STXBP1, and UNC13B to be associated with migraine. CONCLUSIONS Overall, this study provides a new insight into migraine liability, identifying possible starting points for functional studies.
Collapse
Affiliation(s)
- Marlene Quintas
- UnIGENe, IBMC - Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal.,i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,ICBAS - Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - João Luís Neto
- UnIGENe, IBMC - Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal.,i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,ICBAS - Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Jorge Sequeiros
- UnIGENe, IBMC - Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal.,i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,ICBAS - Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Alda Sousa
- UnIGENe, IBMC - Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal.,i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,ICBAS - Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - José Pereira-Monteiro
- UnIGENe, IBMC - Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal.,i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Carolina Lemos
- UnIGENe, IBMC - Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal.,i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,ICBAS - Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Isabel Alonso
- UnIGENe, IBMC - Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal.,i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,ICBAS - Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| |
Collapse
|
|
4
|
Shafquat A, Crystal RG, Mezey JG. Identifying novel associations in GWAS by hierarchical Bayesian latent variable detection of differentially misclassified phenotypes. BMC Bioinformatics 2020; 21:178. [PMID: 32381021 PMCID: PMC7204256 DOI: 10.1186/s12859-020-3387-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 01/24/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Heterogeneity in the definition and measurement of complex diseases in Genome-Wide Association Studies (GWAS) may lead to misdiagnoses and misclassification errors that can significantly impact discovery of disease loci. While well appreciated, almost all analyses of GWAS data consider reported disease phenotype values as is without accounting for potential misclassification. RESULTS Here, we introduce Phenotype Latent variable Extraction of disease misdiagnosis (PheLEx), a GWAS analysis framework that learns and corrects misclassified phenotypes using structured genotype associations within a dataset. PheLEx consists of a hierarchical Bayesian latent variable model, where inference of differential misclassification is accomplished using filtered genotypes while implementing a full mixed model to account for population structure and genetic relatedness in study populations. Through simulations, we show that the PheLEx framework dramatically improves recovery of the correct disease state when considering realistic allele effect sizes compared to existing methodologies designed for Bayesian recovery of disease phenotypes. We also demonstrate the potential of PheLEx for extracting new potential loci from existing GWAS data by analyzing bipolar disorder and epilepsy phenotypes available from the UK Biobank. From the PheLEx analysis of these data, we identified new candidate disease loci not previously reported for these datasets that have value for supplemental hypothesis generation. CONCLUSION PheLEx shows promise in reanalyzing GWAS datasets to provide supplemental candidate loci that are ignored by traditional GWAS analysis methodologies.
Collapse
Affiliation(s)
- Afrah Shafquat
- Department of Computational Biology, Cornell University, Ithaca, NY USA
| | - Ronald G. Crystal
- Department of Genetic Medicine, Weill Cornell Medicine, New York, NY USA
- Department of Medicine, Weill Cornell Medicine, New York, NY USA
| | - Jason G. Mezey
- Department of Computational Biology, Cornell University, Ithaca, NY USA
- Department of Genetic Medicine, Weill Cornell Medicine, New York, NY USA
| |
Collapse
|
|
5
|
Yarwood R, Hellicar J, Woodman PG, Lowe M. Membrane trafficking in health and disease. Dis Model Mech 2020; 13:13/4/dmm043448. [PMID: 32433026 PMCID: PMC7197876 DOI: 10.1242/dmm.043448] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Membrane trafficking pathways are essential for the viability and growth of cells, and play a major role in the interaction of cells with their environment. In this At a Glance article and accompanying poster, we outline the major cellular trafficking pathways and discuss how defects in the function of the molecular machinery that mediates this transport lead to various diseases in humans. We also briefly discuss possible therapeutic approaches that may be used in the future treatment of trafficking-based disorders. Summary: This At a Glance article and poster summarise the major intracellular membrane trafficking pathways and associated molecular machineries, and describe how defects in these give rise to disease in humans.
Collapse
Affiliation(s)
- Rebecca Yarwood
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK
| | - John Hellicar
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK
| | - Philip G Woodman
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK
| | - Martin Lowe
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK
| |
Collapse
|
|
6
|
Pogorelov VM, Kao HT, Augustine GJ, Wetsel WC. Postsynaptic Mechanisms Render Syn I/II/III Mice Highly Responsive to Psychostimulants. Int J Neuropsychopharmacol 2019; 22:453-465. [PMID: 31188434 PMCID: PMC6600466 DOI: 10.1093/ijnp/pyz019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/11/2019] [Accepted: 04/23/2019] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Synapsins are encoded by SYN I, SYN II, and SYN III, and they regulate neurotransmitter release by maintaining a reserve pool of synaptic vesicles. METHODS Presynaptic dopamine responses to cocaine were examined by microdialysis, and postsynaptic responses were evaluated to various dopamine receptor agonists in the open field with SynI/SynII/SynIII triple knockout mice. RESULTS Triple knockout mice showed enhanced spontaneous locomotion in a novel environment and were hyper-responsive to indirect and direct D1 and D2 dopamine agonists. Triple knockout animals appeared sensitized to cocaine upon first open field exposure; sensitization developed across days in wild-type controls. When mutants were preexposed to a novel environment before injection, cocaine-stimulated locomotion was reduced and behavioral sensitization retarded. Baseline dopamine turnover was enhanced in mutants and novel open field exposure increased their striatal dopamine synthesis rates. As KCl-depolarization stimulated comparable dopamine release in both genotypes, their readily releasable pools appeared indistinguishable. Similarly, cocaine-induced hyperlocomotion was indifferent to blockade of newly synthesized dopamine and depletion of releasable dopamine pools. Extracellular dopamine release was similar in wild-type and triple knockout mice preexposed to the open field and given cocaine or placed immediately into the arena following injection. Since motor effects to novelty and psychostimulants depend upon frontocortical-striatal inputs, we inhibited triple knockout medial frontal cortex with GABA agonists. Locomotion was transiently increased in cocaine-injected mutants, while their supersensitive cocaine response to novelty was lost. CONCLUSIONS These results reveal presynaptic dopamine release is not indicative of agonist-induced triple knockout hyperlocomotion. Instead, their novelty response occurs primarily through postsynaptic mechanisms and network effects.
Collapse
Affiliation(s)
- Vladimir M Pogorelov
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina
| | - Hung-Teh Kao
- Department of Psychiatry and Human Behavior, Brown University, BioMedical Center, Providence, Rhode Island
| | - George J Augustine
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore and the Institute of Molecular and Cellular Biology, Singapore, Singapore
| | - William C Wetsel
- Departments of Cell Biology and Neurobiology, Duke University Medical Center, Durham, North Carolina,Correspondence: William C. Wetsel, PhD, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, 354 Sands Building, P.O. Box 103203, 333 Research Drive, Durham, NC 27710 ()
| |
Collapse
|
|
7
|
Mirza FJ, Zahid S. The Role of Synapsins in Neurological Disorders. Neurosci Bull 2017; 34:349-358. [PMID: 29282612 DOI: 10.1007/s12264-017-0201-7] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 10/27/2017] [Indexed: 12/12/2022] Open
Abstract
Synapsins serve as flagships among the presynaptic proteins due to their abundance on synaptic vesicles and contribution to synaptic communication. Several studies have emphasized the importance of this multi-gene family of neuron-specific phosphoproteins in maintaining brain physiology. In the recent times, increasing evidence has established the relevance of alterations in synapsins as a major determinant in many neurological disorders. Here, we give a comprehensive description of the diverse roles of the synapsin family and the underlying molecular mechanisms that contribute to several neurological disorders. These physiologically important roles of synapsins associated with neurological disorders are just beginning to be understood. A detailed understanding of the diversified expression of synapsins may serve to strategize novel therapeutic approaches for these debilitating neurological disorders.
Collapse
Affiliation(s)
- Fatima Javed Mirza
- Neurobiology Research Laboratory, Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Saadia Zahid
- Neurobiology Research Laboratory, Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan.
| |
Collapse
|
|
8
|
Abstract
Over the last decade, the apparent increase in placebo responses in randomized controlled trials (RCTs) of neuropathic pain have complicated and potentially limited development and availability of new effective pain medication. Placebo analgesia and nocebo hyperalgesia effects are well described in nociceptive and idiopathic pain conditions, but less is known about the magnitude and mechanisms of placebo and nocebo effects in neuropathic pain. In neuropathic pain, placebo treatments have primarily been used as control conditions for active agents under investigation in RCTs and these placebo responses are typically not controlled for the natural history of pain and other confounding factors. Recently, mechanistic studies that control for the natural history of pain have investigated placebo and nocebo effects in neuropathic pain in their own right. Large placebo analgesia but no nocebo hyperalgesic effects have been found, and the underlying mechanisms are beginning to be elucidated. Here we review placebo and nocebo effects and the underlying mechanisms in neuropathic pain and compare them with those of nociceptive and idiopathic pain. This allows for a novel discussion on how knowledge of psychological, neurobiological, and genetic factors underlying well-controlled placebo effects may help improve the information that can be obtained from and potentially restore the utility of RCTs.
Collapse
|
|
9
|
Molinaro L, Hui P, Tan M, Mishra RK. Role of presynaptic phosphoprotein synapsin II in schizophrenia. World J Psychiatry 2015; 5:260-272. [PMID: 26425441 PMCID: PMC4582303 DOI: 10.5498/wjp.v5.i3.260] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 04/30/2015] [Accepted: 06/11/2015] [Indexed: 02/05/2023] Open
Abstract
Synapsin II is a member of the neuronal phosphoprotein family. These phosphoproteins are evolutionarily conserved across many organisms and are important in a variety of synaptic functions, including synaptogenesis and the regulation of neurotransmitter release. A number of genome-wide scans, meta-analyses, and genetic susceptibility studies have implicated the synapsin II gene (3p25) in the etiology of schizophrenia (SZ) and other psychiatric disorders. Further studies have found a reduction of synapsin II mRNA and protein in the prefrontal cortex in post-mortem samples from schizophrenic patients. Disruptions in the expression of this gene may cause synaptic dysfunction, which can result in neurotransmitter imbalances, likely contributing to the pathogenesis of SZ. SZ is a costly, debilitating psychiatric illness affecting approximately 1.1% of the world’s population, amounting to 51 million people today. The disorder is characterized by positive (hallucinations, paranoia), negative (social withdrawal, lack of motivation), and cognitive (memory impairments, attention deficits) symptoms. This review provides a comprehensive summary of the structure, function, and involvement of the synapsin family, specifically synapsin II, in the pathophysiology of SZ and possible target for therapeutic intervention/implications.
Collapse
|
|
10
|
Carrel D, Hernandez K, Kwon M, Mau C, Trivedi MP, Brzustowicz LM, Firestein BL. Nitric oxide synthase 1 adaptor protein, a protein implicated in schizophrenia, controls radial migration of cortical neurons. Biol Psychiatry 2015; 77:969-78. [PMID: 25542305 PMCID: PMC4416077 DOI: 10.1016/j.biopsych.2014.10.016] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 10/08/2014] [Accepted: 10/22/2014] [Indexed: 12/22/2022]
Abstract
BACKGROUND Where a neuron is positioned in the brain during development determines neuronal circuitry and information processing needed for normal brain function. When aberrations in this process occur, cognitive disorders may result. Patients diagnosed with schizophrenia have been reported to show altered neuronal connectivity and heterotopias. To elucidate pathways by which this process occurs and become aberrant, we have chosen to study the long isoform of nitric oxide synthase 1 adaptor protein (NOS1AP), a protein encoded by a susceptibility gene for schizophrenia. METHODS To determine whether NOS1AP plays a role in cortical patterning, we knocked down or co-overexpressed NOS1AP and a green fluorescent protein or red fluorescent protein (TagRFP) reporter in neuronal progenitor cells of the embryonic rat neocortex using in utero electroporation. We analyzed sections of cortex (ventricular zone, intermediate zone, and cortical plate [CP]) containing green fluorescent protein or red fluorescent protein TagRFP positive cells and counted the percentage of positive cells that migrated to each region from at least three rats for each condition. RESULTS NOS1AP overexpression disrupts neuronal migration, resulting in increased cells in intermediate zone and less cells in CP, and decreases dendritogenesis. Knockdown results in increased migration, with more cells reaching the CP. The phosphotyrosine binding region, but not the PDZ-binding motif, is necessary for NOS1AP function. Amino acids 181 to 307, which are sufficient for NOS1AP-mediated decreases in dendrite number, have no effect on migration. CONCLUSIONS Our studies show for the first time a critical role for the schizophrenia-associated gene NOS1AP in cortical patterning, which may contribute to underlying pathophysiology seen in schizophrenia.
Collapse
Affiliation(s)
- Damien Carrel
- Department of Cell Biology and Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey; Neurophotonics Laboratory, Paris Descartes University, Paris, France
| | - Kristina Hernandez
- Department of Cell Biology and Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey; Molecular Biosciences Graduate Program Rutgers, the State University of New Jersey, Piscataway, New Jersey
| | - Munjin Kwon
- Department of Cell Biology and Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey; Molecular Biosciences Graduate Program Rutgers, the State University of New Jersey, Piscataway, New Jersey
| | - Christine Mau
- Department of Cell Biology and Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey
| | - Meera P Trivedi
- Department of Cell Biology and Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey
| | - Linda M Brzustowicz
- Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey
| | - Bonnie L Firestein
- Department of Cell Biology and Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey.
| |
Collapse
|
|
11
|
Basu D, Tian Y, Hui P, Bhandari J, Johnson RL, Mishra RK. Change in expression of vesicular protein synapsin II by chronic treatment with D2 allosteric modulator PAOPA. Peptides 2015; 66:58-62. [PMID: 25703303 DOI: 10.1016/j.peptides.2015.01.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 01/20/2015] [Accepted: 01/20/2015] [Indexed: 12/21/2022]
Abstract
The hallmark symptoms of schizophrenia include profound disturbances in thought, perception, cognition etc., which negatively impacts an individual's quality of life. Current antipsychotic drugs are not effective in treating all symptoms of this disorder, and often cause severe movement and metabolic side effects. Consequently, there remains a strong impetus to develop safer and more efficacious therapeutics for patients, as well as elucidating the etiology of schizophrenia. Previous work in our lab has introduced a novel candidate for the treatment of this disease: the dopamine D2 receptor (D2R) allosteric modulator, 3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide (PAOPA). We have previously shown that PAOPA, by selectively modulating D2R, can ameliorate schizophrenia-like symptoms in animal models, although the precise mechanism is presently not understood. Synapsin II is a presynaptic vesicular protein which has been strongly implicated in schizophrenia, as it is reduced in the prefrontal cortex of patients, and knockdown of this protein elicits schizophrenia-like phenotypes in animal models. Given the therapeutic effects of PAOPA and the role of synapsin II in schizophrenia, the objective of this study was to investigate the effect of chronic administration of PAOPA (45 days) on neuronal synapsin II protein expression in rodents. Immunoblot results revealed that the synapsin IIa, but not the IIb isoform, was increased in the dopaminergic regions of the striatum, nucleus accumbens, and medial prefrontal cortex. The results of this study implicate a role for modulation of synapsin II as a possible therapeutic mechanism of action for potential antipsychotic drug PAOPA.
Collapse
Affiliation(s)
- Dipannita Basu
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1200 Main St. W., Hamilton, ON, Canada L8N 3Z5
| | - Yuxin Tian
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1200 Main St. W., Hamilton, ON, Canada L8N 3Z5
| | - Patricia Hui
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1200 Main St. W., Hamilton, ON, Canada L8N 3Z5
| | - Jayant Bhandari
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1200 Main St. W., Hamilton, ON, Canada L8N 3Z5
| | - Rodney L Johnson
- Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN 55455, USA
| | - Ram K Mishra
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1200 Main St. W., Hamilton, ON, Canada L8N 3Z5.
| |
Collapse
|
|
12
|
Corradi A, Fadda M, Piton A, Patry L, Marte A, Rossi P, Cadieux-Dion M, Gauthier J, Lapointe L, Mottron L, Valtorta F, Rouleau GA, Fassio A, Benfenati F, Cossette P. SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth. Hum Mol Genet 2013; 23:90-103. [PMID: 23956174 PMCID: PMC3857945 DOI: 10.1093/hmg/ddt401] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
An increasing number of genes predisposing to autism spectrum disorders (ASDs) has been identified, many of which are implicated in synaptic function. This 'synaptic autism pathway' notably includes disruption of SYN1 that is associated with epilepsy, autism and abnormal behavior in both human and mice models. Synapsins constitute a multigene family of neuron-specific phosphoproteins (SYN1-3) present in the majority of synapses where they are implicated in the regulation of neurotransmitter release and synaptogenesis. Synapsins I and II, the major Syn isoforms in the adult brain, display partially overlapping functions and defects in both isoforms are associated with epilepsy and autistic-like behavior in mice. In this study, we show that nonsense (A94fs199X) and missense (Y236S and G464R) mutations in SYN2 are associated with ASD in humans. The phenotype is apparent in males. Female carriers of SYN2 mutations are unaffected, suggesting that SYN2 is another example of autosomal sex-limited expression in ASD. When expressed in SYN2 knockout neurons, wild-type human Syn II fully rescues the SYN2 knockout phenotype, whereas the nonsense mutant is not expressed and the missense mutants are virtually unable to modify the SYN2 knockout phenotype. These results identify for the first time SYN2 as a novel predisposing gene for ASD and strengthen the hypothesis that a disturbance of synaptic homeostasis underlies ASD.
Collapse
Affiliation(s)
- Anna Corradi
- Department of Experimental Medicine, University of Genova, Viale Benedetto XV 3, Genova 16132, Italy
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Synapsin II gene expression in the dorsolateral prefrontal cortex of brain specimens from patients with schizophrenia and bipolar disorder: effect of lifetime intake of antipsychotic drugs. THE PHARMACOGENOMICS JOURNAL 2013; 14:63-9. [PMID: 23529008 PMCID: PMC3970980 DOI: 10.1038/tpj.2013.6] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Revised: 01/04/2013] [Accepted: 02/04/2013] [Indexed: 01/31/2023]
Abstract
Synapsins are neuronal phosphoproteins crucial to regulating the processes required for normal neurotransmitter release. Synapsin II, in particular, has been implied as a candidate gene for schizophrenia. This study investigated synapsin II mRNA expression, using Real Time RT-PCR, in coded dorsolateral prefrontal cortical samples provided by the Stanley Foundation Neuropathology Consortium. Synapsin IIa was decreased in patients with schizophrenia when compared to both healthy subjects and patients with bipolar disorder, whereas the synapsin IIb was only significantly reduced in patients with schizophrenia when compared to healthy subjects, but not patients with bipolar disorder. Furthermore, lifetime antipsychotic drug use was positively associated with synapsin IIa expression in patients with schizophrenia. Results suggest that impairment of synaptic transmission by synapsin II reduction may contribute to dysregulated convergent molecular mechanisms which result in aberrant neural circuits that characterize schizophrenia, while implicating involvement of synapsin II in therapeutic mechanisms of currently prescribed antipsychotic drugs.
Collapse
|
|
14
|
H3K4 tri-methylation in synapsin genes leads to different expression patterns in bipolar disorder and major depression. Int J Neuropsychopharmacol 2013; 16:289-99. [PMID: 22571925 PMCID: PMC3564952 DOI: 10.1017/s1461145712000363] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The synapsin family of neuronal phosphoproteins is composed of three genes (SYN1, SYN2 and SYN3) with alternative splicing resulting in a number of variants with various levels of homology. These genes have been postulated to play significant roles in several neuropsychiatric disorders, including bipolar disorder, schizophrenia and epilepsy. Epigenetic regulatory mechanisms, such as histone modifications in gene regulatory regions, have also been proposed to play a role in a number of psychiatric disorders, including bipolar disorder and major depressive disorder. One of the best characterized histone modifications is histone 3 lysine 4 tri-methylation (H3K4me3), an epigenetic mark shown to be highly enriched at transcriptional start sites and associated with active transcription. In the present study we have quantified the expression of transcript variants of the three synapsin genes and investigated their relationship to H3K4me3 promoter enrichment in post-mortem brain samples. We found that histone modification marks were significantly increased in bipolar disorder and major depression and this effect was correlated with significant increases in gene expression. Our findings suggest that synapsin dysregulation in mood disorders is mediated in part by epigenetic regulatory mechanisms.
Collapse
|
|
15
|
Ayalew M, Le-Niculescu H, Levey DF, Jain N, Changala B, Patel SD, Winiger E, Breier A, Shekhar A, Amdur R, Koller D, Nurnberger JI, Corvin A, Geyer M, Tsuang MT, Salomon D, Schork NJ, Fanous AH, O'Donovan MC, Niculescu AB. Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. Mol Psychiatry 2012; 17:887-905. [PMID: 22584867 PMCID: PMC3427857 DOI: 10.1038/mp.2012.37] [Citation(s) in RCA: 311] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2011] [Revised: 02/28/2012] [Accepted: 03/05/2012] [Indexed: 02/07/2023]
Abstract
We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology.
Collapse
Affiliation(s)
- M Ayalew
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
- Indianapolis VA Medical Center, Indianapolis, IN, USA
| | - H Le-Niculescu
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - D F Levey
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - N Jain
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - B Changala
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - S D Patel
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - E Winiger
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - A Breier
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - A Shekhar
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - R Amdur
- Washington DC VA Medical Center, Washington, DC, USA
| | - D Koller
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - J I Nurnberger
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - A Corvin
- Department of Psychiatry, Trinity College, Dublin, Ireland
| | - M Geyer
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
| | - M T Tsuang
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
| | - D Salomon
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA
| | - N J Schork
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA
| | - A H Fanous
- Washington DC VA Medical Center, Washington, DC, USA
| | - M C O'Donovan
- Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, UK
| | - A B Niculescu
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
- Indianapolis VA Medical Center, Indianapolis, IN, USA
| |
Collapse
|
|
16
|
Long-lasting hippocampal synaptic protein loss in a mouse model of posttraumatic stress disorder. PLoS One 2012; 7:e42603. [PMID: 22900032 PMCID: PMC3416820 DOI: 10.1371/journal.pone.0042603] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Accepted: 07/09/2012] [Indexed: 01/08/2023] Open
Abstract
Despite intensive research efforts, the molecular pathogenesis of posttraumatic stress disorder (PTSD) and especially of the hippocampal volume loss found in the majority of patients suffering from this anxiety disease still remains elusive. We demonstrated before that trauma-induced hippocampal shrinkage can also be observed in mice exhibiting a PTSD-like syndrome. Aiming to decipher the molecular correlates of these trans-species posttraumatic hippocampal alterations, we compared the expression levels of a set of neurostructural marker proteins between traumatized and control mice at different time points after their subjection to either an electric footshock or mock treatment which was followed by stressful re-exposure in several experimental groups. To our knowledge, this is the first systematic in vivo study analyzing the long-term neuromolecular sequelae of acute traumatic stress combined with re-exposure. We show here that a PTSD-like syndrome in mice is accompanied by a long-lasting reduction of hippocampal synaptic proteins which interestingly correlates with the strength of the generalized and conditioned fear response but not with the intensity of hyperarousal symptoms. Furthermore, we demonstrate that treatment with the serotonin reuptake inhibitor (SSRI) fluoxetine is able to counteract both the PTSD-like syndrome and the posttraumatic synaptic protein loss. Taken together, this study demonstrates for the first time that a loss of hippocampal synaptic proteins is associated with a PTSD-like syndrome in mice. Further studies will have to reveal whether these findings are transferable to PTSD patients.
Collapse
|
|
17
|
Crisafulli C, Chiesa A, Han C, Lee SJ, Park MH, Balzarro B, Andrisano C, Patkar AA, Pae CU, Serretti A. Case-control association study for 10 genes in patients with schizophrenia: influence of 5HTR1A variation rs10042486 on schizophrenia and response to antipsychotics. Eur Arch Psychiatry Clin Neurosci 2012; 262:199-205. [PMID: 22120873 DOI: 10.1007/s00406-011-0278-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Accepted: 11/17/2011] [Indexed: 11/28/2022]
Abstract
The aim of this study is to investigate possible associations between a set of single-nucleotide polymorphisms (SNPs) within 10 genes with Schizophrenia (SCZ) and response to antipsychotics in Korean in-patients treated with antipsychotics. Two hundred and twenty-one SCZ in-patients and 170 psychiatrically healthy controls were genotyped for 42 SNPs within ABCB1, ABCB4, TAP2, CLOCK, CPLX1, CPLX2, SYN2, NRG1, 5HTR1A and GPRIN2. Baseline and final clinical measures, including the Positive and Negative Symptoms Scale (PANSS), were recorded. Rs10042486 within 5HTR1A was associated with both SCZ and clinical improvement on PANSS total scores as well as on PANSS positive and PANSS negative scores. The haplotype analyses focusing on the four, three and two blocks' haplotypes within 5HTR1A confirmed such findings as well. We did not observe any significant association between the remaining genetic variants under investigation in this study and clinical outcomes. Our preliminary findings suggest that rs10042486 within 5HTR1A promoter region could be associated with SCZ and with clinical improvement on PANSS total, positive and negative scores in Korean patients with SCZ. However, taking into account the several limitations of our study, further research is needed to draw more definitive conclusions.
Collapse
Affiliation(s)
- Concetta Crisafulli
- Department of Biomorphology and Biotechnologies, Division of Biology and Genetics, University of Messina, Italy
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Cruceanu C, Alda M, Grof P, Rouleau GA, Turecki G. Synapsin II is involved in the molecular pathway of lithium treatment in bipolar disorder. PLoS One 2012; 7:e32680. [PMID: 22384280 PMCID: PMC3286475 DOI: 10.1371/journal.pone.0032680] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Accepted: 01/28/2012] [Indexed: 01/06/2023] Open
Abstract
Bipolar disorder (BD) is a debilitating psychiatric condition with a prevalence of 1–2% in the general population that is characterized by severe episodic shifts in mood ranging from depressive to manic episodes. One of the most common treatments is lithium (Li), with successful response in 30–60% of patients. Synapsin II (SYN2) is a neuronal phosphoprotein that we have previously identified as a possible candidate gene for the etiology of BD and/or response to Li treatment in a genome-wide linkage study focusing on BD patients characterized for excellent response to Li prophylaxis. In the present study we investigated the role of this gene in BD, particularly as it pertains to Li treatment. We investigated the effect of lithium treatment on the expression of SYN2 in lymphoblastoid cell lines from patients characterized as excellent Li-responders, non-responders, as well as non-psychiatric controls. Finally, we sought to determine if Li has a cell-type-specific effect on gene expression in neuronal-derived cell lines. In both in vitro models, we found SYN2 to be modulated by the presence of Li. By focusing on Li-responsive BD we have identified a potential mechanism for Li response in some patients.
Collapse
Affiliation(s)
- Cristiana Cruceanu
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada
| | - Martin Alda
- Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Paul Grof
- Mood Disorders Centre of Ottawa, Ottawa, Ontario, Canada
| | - Guy A. Rouleau
- Centre of Excellence in Neuromics, CHUM Research Center and the Department of Medicine, University of Montreal, Montreal, Quebec, Canada
| | - Gustavo Turecki
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada
- * E-mail:
| |
Collapse
|
|
19
|
Powell SB, Weber M, Geyer MA. Genetic models of sensorimotor gating: relevance to neuropsychiatric disorders. Curr Top Behav Neurosci 2012; 12:251-318. [PMID: 22367921 PMCID: PMC3357439 DOI: 10.1007/7854_2011_195] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Sensorimotor gating, or the ability of a sensory event to suppress a motor response, can be measured operationally via prepulse inhibition (PPI) of the startle response. PPI is deficient in schizophrenia patients as well as other neuropsychiatric disorders, can be measured across species, and has been used widely as a translational tool in preclinical neuropharmacological and genetic research. First developed to assess drug effects in pharmacological and developmental models, PPI has become one of the standard behavioral measures in genetic models of schizophrenia and other neuropsychiatric disorders that exhibit PPI deficits. In this chapter we review the literature on genetic models of sensorimotor gating and discuss the utility of PPI as a tool in phenotyping mutant mouse models. We highlight the approaches to genetic mouse models of neuropsychiatric disease, discuss some of the important caveats to these approaches, and provide a comprehensive table covering the more recent genetic models that have evaluated PPI.
Collapse
Affiliation(s)
- Susan B. Powell
- Department of Psychiatry, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0804, USA
- Research Service, VA San Diego Healthcare System, San Diego, CA, USA
| | - Martin Weber
- Department of Neuroscience, Genentech Inc, 1 DNA Way, South San Francisco, CA 94080-4990, USA
| | - Mark A. Geyer
- Department of Psychiatry, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0804, USA
- Research Service, VA San Diego Healthcare System, San Diego, CA, USA
| |
Collapse
|
|
20
|
Evidence for disease and antipsychotic medication effects in post-mortem brain from schizophrenia patients. Mol Psychiatry 2011; 16:1189-202. [PMID: 20921955 DOI: 10.1038/mp.2010.100] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Extensive research has been conducted on post-mortem brain tissue in schizophrenia (SCZ), particularly the dorsolateral prefrontal cortex (DLPFC). However, to what extent the reported changes are due to the disorder itself, and which are the cumulative effects of lifetime medication remains to be determined. In this study, we employed label-free liquid chromatography-mass spectrometry-based proteomic and proton nuclear magnetic resonance-based metabonomic profiling approaches to investigate DLPFC tissue from two cohorts of SCZ patients grouped according to their lifetime antipsychotic dose, together with tissue from bipolar disorder (BPD) subjects, and normal controls (n=10 per group). Both techniques showed profound changes in tissue from low-cumulative-medication SCZ subjects, but few changes in tissue from medium-cumulative-medication subjects. Protein expression changes were validated by Western blot and investigated further in a third group of subjects who were subjected to high-cumulative-medication over the course of their lifetime. Furthermore, key protein expression and metabolite level changes correlated significantly with lifetime antipsychotic dose. This suggests that the detected changes are present before antipsychotic therapy and, moreover, may be normalized with treatment. Overall, our analyses revealed novel protein and metabolite changes in low-cumulative-medication subjects associated with synaptogenesis, neuritic dynamics, presynaptic vesicle cycling, amino acid and glutamine metabolism, and energy buffering systems. Most of these markers were altered specifically in SCZ as determined by analysis of the same brain region from BPD patients.
Collapse
|
|
21
|
Di Domenico F, Casalena G, Sultana R, Cai J, Pierce WM, Perluigi M, Cini C, Baracca A, Solaini G, Lenaz G, Jia J, Dziennis S, Murphy SJ, Alkayed NJ, Butterfield DA. Involvement of Stat3 in mouse brain development and sexual dimorphism: a proteomics approach. Brain Res 2010; 1362:1-12. [PMID: 20875800 PMCID: PMC2975791 DOI: 10.1016/j.brainres.2010.09.074] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2010] [Revised: 09/16/2010] [Accepted: 09/20/2010] [Indexed: 01/27/2023]
Abstract
Although the role of STAT3 in cell physiology and tissue development has been largely investigated, its involvement in the development and maintenance of nervous tissue and in the mechanisms of neuroprotection is not yet known. The potentially wide range of STAT3 activities raises the question of tissue- and gender-specificity as putative mechanisms of regulation. To explore the function of STAT3 in the brain and the hypothesis of a gender-linked modulation of STAT3, we analyzed a neuron-specific STAT3 knockout mouse model investigating the influence of STAT3 activity in brain protein expression pattern in both males and females in the absence of neurological insult. We performed a proteomic study aimed to reveal the molecular pathways directly or indirectly controlled by STAT3 underscoring its role in brain development and maintenance. We identified several proteins, belonging to different neuronal pathways such as energy metabolism or synaptic transmission, controlled by STAT3 that confirm its crucial role in brain development and maintenance. Moreover, we investigated the different processes that could contribute to the sexual dimorphic behavior observed in the incidence of neurological and mental disease. Interestingly both STAT3 KO and gender factors influence the expression of several mitochondrial proteins conferring to mitochondrial activity high importance in the regulation of brain physiology and conceivable relevance as therapeutic target.
Collapse
Affiliation(s)
- Fabio Di Domenico
- Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington KY 40506-0055
- Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Gabriella Casalena
- Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington KY 40506-0055
- Department of Biochemistry "G. Moruzzi", University of Bologna, 40126 Bologna, Italy
| | - Rukhsana Sultana
- Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington KY 40506-0055
| | - Jian Cai
- Department of Pharmacology, University of Louisville, Louisville, KY
| | - William M. Pierce
- Department of Pharmacology, University of Louisville, Louisville, KY
| | - Marzia Perluigi
- Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Chiara Cini
- Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Alessandra Baracca
- Department of Biochemistry "G. Moruzzi", University of Bologna, 40126 Bologna, Italy
| | - Giancarlo Solaini
- Department of Biochemistry "G. Moruzzi", University of Bologna, 40126 Bologna, Italy
| | - Giorgio Lenaz
- Department of Biochemistry "G. Moruzzi", University of Bologna, 40126 Bologna, Italy
| | - Jia Jia
- Department of Anesthesiology & Peri-Operative Medicine, Oregon Health & Science University, Portland, OR 97239-3098, USA
| | - Suzan Dziennis
- Department of Anesthesiology & Peri-Operative Medicine, Oregon Health & Science University, Portland, OR 97239-3098, USA
| | - Stephanie J. Murphy
- Department of Anesthesiology & Peri-Operative Medicine, Oregon Health & Science University, Portland, OR 97239-3098, USA
| | - Nabil J. Alkayed
- Department of Anesthesiology & Peri-Operative Medicine, Oregon Health & Science University, Portland, OR 97239-3098, USA
| | - D. Allan Butterfield
- Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington KY 40506-0055
| |
Collapse
|
|
22
|
Lakhan R, Kalita J, Misra UK, Kumari R, Mittal B. Association of intronic polymorphism rs3773364 A>G in synapsin-2 gene with idiopathic epilepsy. Synapse 2010; 64:403-408. [PMID: 20034013 DOI: 10.1002/syn.20740] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
In epilepsy, there is a tendency towards recurrent unprovoked seizures. Seizures result due to the excessive electrical misfiring in the brain between neurons and disturbance in neurotransmitter release. Several gene products affect the behavior of these neurons by regulating neurotransmission via several mechanisms. One such gene, Synapsin-2 (SYN2), involved in synaptogenesis is also reported to regulate the neurotransmitter release. We hypothesized that SYN2 gene and its polymorphisms could affect the process of epileptogenesis and therapeutic response in humans. In this hospital-based study, we enrolled 372 patients with epilepsy and 199 control subjects. We selected rs3773364 A>G polymorphism in SYN2 gene and analyzed its distribution in north Indian patients with epilepsy and control subjects. Genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. According to the results obtained, SYN2 "AG" genotype frequency was significantly higher in patients with epilepsy versus control subjects in north Indian population (P = 0.02, OR = 1.55, 95% CI = 1.06-2.26). After subclassification, we observed higher frequency of AG genotype in idiopathic patients as compared to control subjects (P = 0.01, OR = 1.67, 95% CI = 1.08-2.56). There were no significant differences in genotypic (AG: OR = 0.80, P = 0.377; GG: P = 0.628, OR = 1.17) or allelic (P = 0.86, OR = 1.03) frequency distributions in patients with multiple drug resistance versus patients with drug-responsive epilepsy. Results from our study indicate the involvement of SYN2 gene polymorphism in conferring risk to epilepsy; however, the genetic variant does not seem to modulate drug-response in epilepsy pharmacotherapy.
Collapse
Affiliation(s)
- Ram Lakhan
- Department of Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India
| | | | | | | | | |
Collapse
|
|
23
|
Association study and mutational screening of SYNGR1 as a candidate susceptibility gene for schizophrenia. Psychiatr Genet 2009; 19:237-43. [DOI: 10.1097/ypg.0b013e32832cebf7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
24
|
Wang Y, Yu L, Zhao T, Xu J, Liu Z, Liu Y, Feng G, He L, Li S. No association between bipolar disorder and syngr1 or synapsin II polymorphisms in the Han Chinese population. Psychiatry Res 2009; 169:167-8. [PMID: 19665806 DOI: 10.1016/j.psychres.2008.12.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2008] [Revised: 10/30/2008] [Accepted: 12/22/2008] [Indexed: 11/30/2022]
Abstract
Polymorphisms of the SYNAPTOGYRIN1 (SYNGR1) and SYNASINII (SYNII) genes have been shown to be a risk factor for bipolar disorder or schizophrenia. A case-control study with these two genes was conducted in 506 bipolar disorder patients and 507 healthy individuals from the Han Chinese population. No association was found in this study.
Collapse
Affiliation(s)
- Yabing Wang
- Institute for Nutritional Sciences, SIBS, Chinese Academy of Sciences, Shanghai 200031, PR China; Bio-X Center, Shanghai Jiao Tong University, Shanghai 200030, PR China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Dong Y, Zhang H, Wang X, Feng Q, Chen X, Su Q. A Leu184Val polymorphism in PCK1 gene is associated with type 2 diabetes in Eastern Chinese population with BMI<23 kg/m2. Diabetes Res Clin Pract 2009; 83:227-32. [PMID: 19070910 DOI: 10.1016/j.diabres.2008.10.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2008] [Revised: 09/07/2008] [Accepted: 10/20/2008] [Indexed: 10/21/2022]
Abstract
Our previous finding has shown that a suggestive linkage existed in D20S196 in diabetic families with lowered BMI in eastern Chinese population. The aim of this study is to investigate whether variants in PCK1 gene, located in this region, was associated with type 2 diabetes in eastern China. Eleven SNPs were identified by sequencing in PCK1. The G (Val184) allele of rs707555 (Leu184Val) in diabetic group was associated with type 2 diabetes (P=0.015; odds ratio 1.42 [95% CI 1.08-1.88]), and was much stronger in subgroup with the BMI<23kg/m(2) (P=0.008). rs2070755, located in intron 4, was also associated with type 2 diabetes (P=0.037; odds ratio 1.29 [95% CI 1.03-1.64]), especially in subgroup with the BMI<23 kg/m(2) (P=0.018). The enzymatic activity of PEPCK-C containing Leu184 was higher than that of PEPCK-C containing Val184 (P<0.01). These results showed that Val184 of PCK1 gene might increase the risk of type 2 diabetes in eastern Chinese population with BMI<23 kg/m(2) via reducing the PEPCK-C activity.
Collapse
Affiliation(s)
- Yan Dong
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
| | | | | | | | | | | |
Collapse
|
|
26
|
Gerber B, Stocker RF, Tanimura T, Thum AS. Smelling, tasting, learning: Drosophila as a study case. Results Probl Cell Differ 2009; 47:139-185. [PMID: 19145411 DOI: 10.1007/400_2008_9] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Understanding brain function is to account for how the sensory system is integrated with the organism's needs to organize behaviour. We review what is known about these processes with regard to chemosensation and chemosensory learning in Drosophila. We stress that taste and olfaction are organized rather differently. Given that, e.g., sugars are nutrients and should be eaten (irrespective of the kind of sugar) and that toxic substances should be avoided (regardless of the kind of death they eventually cause), tastants are classified into relatively few behavioural matters of concern. In contrast, what needs to be done in response to odours is less evolutionarily determined. Thus, discrimination ability is warranted between different kinds of olfactory input, as any difference between odours may potentially be or become important. Therefore, the olfactory system has a higher dimensionality than gustation, and allows for more sensory-motor flexibility to attach acquired behavioural 'meaning' to odours. We argue that, by and large, larval and adult Drosophila are similar in these kinds of architecture, and that additionally there are a number of similarities to vertebrates, in particular regarding the cellular architecture of the olfactory pathway, the functional slant of the taste and smell systems towards classification versus discrimination, respectively, and the higher plasticity of the olfactory sensory-motor system. From our point of view, the greatest gap in understanding smell and taste systems to date is not on the sensory side, where indeed impressive advances have been achieved; also, a satisfying account of associative odour-taste memory trace formation seems within reach. Rather, we lack an understanding as to how sensory and motor formats of processing are centrally integrated, and how adaptive motor patterns actually are selected. Such an understanding, we believe, will allow the analysis to be extended to the motivating factors of behaviour, eventually leading to a comprehensive account of those systems which make Drosophila do what Drosophila's got to do.
Collapse
Affiliation(s)
- B Gerber
- Universität Würzburg, Biozentrum, Am Hubland, Würzburg, 97074, Germany.
| | | | | | | |
Collapse
|
|
27
|
Velho TAF, Mello CV. Synapsins are late activity-induced genes regulated by birdsong. J Neurosci 2008; 28:11871-82. [PMID: 19005052 PMCID: PMC2610538 DOI: 10.1523/jneurosci.2307-08.2008] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2008] [Revised: 09/04/2008] [Accepted: 09/26/2008] [Indexed: 11/21/2022] Open
Abstract
The consolidation of long-lasting sensory memories requires the activation of gene expression programs in the brain. Despite considerable knowledge about the early components of this response, little is known about late components (i.e., genes regulated 2-6 h after stimulation) and the relationship between early and late genes. Birdsong represents one of the best natural behaviors to study sensory-induced gene expression in awake, freely behaving animals. Here we show that the expression of several isoforms of synapsins, a group of phosphoproteins thought to regulate the dynamics of synaptic vesicle storage and release, is induced by auditory stimulation with birdsong in the caudomedial nidopallium (NCM) of the zebra finch (Taeniopygia guttata) brain. This induction occurs mainly in excitatory (non-GABAergic) neurons and is modulated (suppressed) by early song-inducible proteins. We also show that ZENK, an early song-inducible transcription factor, interacts with the syn3 promoter in vivo, consistent with a direct regulatory effect and an emerging novel view of ZENK action. These results demonstrate that synapsins are a late component of the genomic response to neuronal activation and that their expression depends on a complex set of regulatory interactions between early and late regulated genes.
Collapse
Affiliation(s)
- Tarciso A. F. Velho
- Department of Behavioral Neuroscience, Oregon Health and Science University, Beaverton, Oregon 97006
| | - Claudio V. Mello
- Department of Behavioral Neuroscience, Oregon Health and Science University, Beaverton, Oregon 97006
| |
Collapse
|
|
28
|
Irmansyah, Schwab SG, Heriani, Handoko HY, Kusumawardhani A, Widyawati I, Amir N, Nasrun MWS, Holmans P, Knapp M, Wildenauer DB. Genome-wide scan in 124 Indonesian sib-pair families with schizophrenia reveals genome-wide significant linkage to a locus on chromosome 3p26-21. Am J Med Genet B Neuropsychiatr Genet 2008; 147B:1245-52. [PMID: 18449910 DOI: 10.1002/ajmg.b.30763] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Variation in incidence of schizophrenia between populations with different ethnical background may reflect population specific differences in nature and composition of genetic and environmental factors. In order to investigate whether there are population specific susceptibility genes for schizophrenia, we collected in Indonesia families with two or more affected siblings and, as far as available, parents and unaffected siblings, suitable for genetic linkage- and association studies. After checking extensively for incompatibilities with Mendelian inheritance as well as for errors in sampling, we used 124 families from the sample of 152 originally ascertained families for linkage analysis. Genotyping was performed at the NHLBI Mammalian Genotyping Service at Marshfield Research Organisation using the Screening Set 16, which comprises 402 Short Tandem Repeat Polymorphisms (STRPs). The genotypes of 540 individuals including 267 affected with schizophrenia were used for analysis. Multipoint sib-pair linkage analysis was carried out by estimation of--allele sharing derived--maximum likelihood LOD scores (MLS) in 154 sib-pair combinations. We obtained a genome-wide significant MLS of 3.76 on chromosome 3p26.2-25.3. Genome-wide significance was estimated by performing 10,000 simulated genomescans. Additional loci were detected on 1p12, which produced suggestive evidence for linkage (MLS = 2.35), as well as on 5q14.1 (MLS = 1.56), 5q33.3 (MLS = 1.11), and 10q (MLS = 1.17), where linkage had been reported previously. In conclusion, our study detected a region with genome-wide significant linkage, which will serve as starting point for identification of schizophrenia susceptibility genes in the Indonesian population.
Collapse
|
|
29
|
Corradi A, Zanardi A, Giacomini C, Onofri F, Valtorta F, Zoli M, Benfenati F. Synapsin-I- and synapsin-II-null mice display an increased age-dependent cognitive impairment. J Cell Sci 2008; 121:3042-51. [PMID: 18713831 DOI: 10.1242/jcs.035063] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2025] Open
Abstract
Synapsin I (SynI) and synapsin II (SynII) are major synaptic vesicle (SV) proteins that function in the regulation of the availability of SVs for release in mature neurons. SynI and SynII show a high level of sequence similarity and share many functions in vivo, although distinct physiological roles for the two proteins have been proposed. Both SynI(-/-) and SynII(-/-) mice have a normal lifespan, but exhibit a decreased number of SVs and synaptic depression upon high-frequency stimulation. Because of the role of the synapsin proteins in synaptic organization and plasticity, we studied the long-lasting effects of synapsin deletion on the phenotype of SynI(-/-) and SynII(-/-) mice during aging. Both SynI(-/-) and SynII(-/-) mice displayed behavioural defects that emerged during aging and involved emotional memory in both mutants, and spatial memory in SynII(-/-) mice. These abnormalities, which were more pronounced in SynII(-/-) mice, were associated with neuronal loss and gliosis in the cerebral cortex and hippocampus. The data indicate that SynI and SynII have specific and non-redundant functions, and that synaptic dysfunctions associated with synapsin mutations negatively modulate cognitive performances and neuronal survival during senescence.
Collapse
Affiliation(s)
- Anna Corradi
- Department of Experimental Medicine, University of Genova and Istituto Nazionale di Neuroscienze, Viale Benedetto XV, 3 16132 Genova, Italy
| | | | | | | | | | | | | |
Collapse
|
|
30
|
Li J. Recent progress in the research field of neuropharmacology in China. Cell Mol Neurobiol 2008; 28:185-204. [PMID: 18240016 PMCID: PMC11515025 DOI: 10.1007/s10571-007-9252-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2007] [Accepted: 12/03/2007] [Indexed: 01/23/2023]
Abstract
In recent years, Chinese neuropharmacologists have done a lot of basic and practical work in neuropharmacology, especially in the fields of pain, drug dependence, depression, Alzheimer's disease, schizophrenia, having obtained some exciting results that are of great significance for the development of neuropharmacology. Here I would like to review recent progress in the research fields of neuropharmacology in China.
Collapse
Affiliation(s)
- Jin Li
- Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
| |
Collapse
|
|
31
|
Saviouk V, Moreau MP, Tereshchenko IV, Brzustowicz LM. Association of synapsin 2 with schizophrenia in families of Northern European ancestry. Schizophr Res 2007; 96:100-11. [PMID: 17766091 PMCID: PMC2169360 DOI: 10.1016/j.schres.2007.07.031] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2007] [Revised: 07/27/2007] [Accepted: 07/31/2007] [Indexed: 12/21/2022]
Abstract
The synapsin 2 (Syn2) gene (3p25) is implicated in synaptogenesis, neurotransmitter release, and the localization of nitric oxide synthase to the proximity of its targets. In this study we investigated linkage and association between the Syn2 locus and schizophrenia. 37 pedigrees of Northern European ancestry from the NIMH Human Genetics Initiative collection were used. Four microsatellites and twenty SNPs were genotyped. Linkage (FASTLINK) and association (TRANSMIT, PDTPHASE) between markers and schizophrenia were evaluated. A maximum heterogeneity LOD of 1.93 was observed at marker D3S3434 with a recessive mode of inheritance. Significant results were obtained for association with schizophrenia using TRANSMIT (minimum nominal p=0.0000005) and PDTPHASE (minimum nominal p=0.014) using single marker analyses. Haplotype analysis using markers in introns 5 and 6 of Syn2 provided a single haplotype that is significantly associated with schizophrenia using TRANSMIT (nominal p<0.00000001) and PDTPHASE (nominal p=0.02). Simulation studies confirm the global significance of these results, but demonstrate that the small p-values generated by the bootstrap routine of TRANSMIT can be consistently anticonservative. Review of the literature suggests that Syn2 is likely to be involved in the etiology or pathogenesis of schizophrenia.
Collapse
|
|
32
|
Behan ÁT, Foy M, Wynne K, Clarke M, Sullivan M, Cotter DR, Maguire PB. Analysis of membrane microdomain-associated proteins in the insular cortex of post-mortem human brain. Proteomics Clin Appl 2007; 1:1324-31. [DOI: 10.1002/prca.200700047] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2007] [Indexed: 12/26/2022]
|
|
33
|
Thomas EA. Molecular profiling of antipsychotic drug function: convergent mechanisms in the pathology and treatment of psychiatric disorders. Mol Neurobiol 2007; 34:109-28. [PMID: 17220533 DOI: 10.1385/mn:34:2:109] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2006] [Revised: 11/30/1999] [Accepted: 06/21/2006] [Indexed: 02/05/2023]
Abstract
Despite great progress in antipsychotic drug research, the molecular mechanisms by which these drugs work have remained elusive. High-throughput gene profiling methods have advanced this field by allowing the simultaneous investigation of hundreds to thousands of genes. However, different methodologies, choice of brain region, and drugs studied have made comparisons across different studies difficult. Because of the complexity of gene expression changes caused by drugs, teasing out the most relevant expression differences is a challenging task. One approach is to focus on gene expression changes that converge on the same systems that were previously deemed important to the pathology of psychiatric disorders. From the microarray studies performed on human postmortem brain samples from schizophrenics, the systems most implicated to be dysfunctional are synaptic machinery, oligodendrocyte/myelin function, and mitochondrial/ubiquitin metabolism. Drugs may act directly or indirectly to compensate for underlying pathological deficits in schizophrenia or via other mechanisms that converge on these pathways. Side effects, consisting of motor and metabolic dysfunction (which occur with typical and atypical drugs, respectively), also may be mediated by gene expression changes that have been reported in these studies. This article surveys both the convergent antipsychotic mechanisms and the genes that may be responsible for other effects elicited by antipsychotic drugs.
Collapse
Affiliation(s)
- Elizabeth A Thomas
- Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA.
| |
Collapse
|
|
34
|
Le-Niculescu H, Balaraman Y, Patel S, Tan J, Sidhu K, Jerome RE, Edenberg HJ, Kuczenski R, Geyer MA, Nurnberger JI, Faraone SV, Tsuang MT, Niculescu AB. Towards understanding the schizophrenia code: an expanded convergent functional genomics approach. Am J Med Genet B Neuropsychiatr Genet 2007; 144B:129-58. [PMID: 17266109 DOI: 10.1002/ajmg.b.30481] [Citation(s) in RCA: 102] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Identifying genes for schizophrenia through classical genetic approaches has proven arduous. Here, we present a comprehensive convergent analysis that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a psychomimetic agent - phencyclidine (PCP), and an anti-psychotic - clozapine), with human genetic linkage data and human postmortem brain data, as a Bayesian strategy of cross validating findings. Topping the list of candidate genes, we have three genes involved in GABA neurotransmission (GABRA1, GABBR1, and GAD2), one gene involved in glutamate neurotransmission (GRIA2), one gene involved in neuropeptide signaling (TAC1), two genes involved in synaptic function (SYN2 and KCNJ4), six genes involved in myelin/glial function (CNP, MAL, MBP, PLP1, MOBP and GFAP), and one gene involved in lipid metabolism (LPL). These data suggest that schizophrenia is primarily a disorder of brain functional and structural connectivity, with GABA neurotransmission playing a prominent role. These findings may explain the EEG gamma band abnormalities detected in schizophrenia. The analysis also revealed other high probability candidates genes (neurotransmitter signaling, other structural proteins, ion channels, signal transduction, regulatory enzymes, neuronal migration/neurite outgrowth, clock genes, transcription factors, RNA regulatory genes), pathways and mechanisms of likely importance in pathophysiology. Some of the pathways identified suggest possible avenues for augmentation pharmacotherapy of schizophrenia with other existing agents, such as benzodiazepines, anticonvulsants and lipid modulating agents. Other pathways are new potential targets for drug development. Lastly, a comparison with our earlier work on bipolar disorder illuminates the significant molecular overlap between schizophrenia and bipolar disorder.
Collapse
Affiliation(s)
- H Le-Niculescu
- Laboratory of Neurophenomics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Gerber B, Stocker RF. The Drosophila larva as a model for studying chemosensation and chemosensory learning: a review. Chem Senses 2006; 32:65-89. [PMID: 17071942 DOI: 10.1093/chemse/bjl030] [Citation(s) in RCA: 170] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Understanding the relationship between brain and behavior is the fundamental challenge in neuroscience. We focus on chemosensation and chemosensory learning in larval Drosophila and review what is known about its molecular and cellular bases. Detailed analyses suggest that the larval olfactory system, albeit much reduced in cell number, shares the basic architecture, both in terms of receptor gene expression and neuronal circuitry, of its adult counterpart as well as of mammals. With respect to the gustatory system, less is known in particular with respect to processing of gustatory information in the central nervous system, leaving generalizations premature. On the behavioral level, a learning paradigm for the association of odors with food reinforcement has been introduced. Capitalizing on the knowledge of the chemosensory pathways, we review the first steps to reveal the genetic and cellular bases of olfactory learning in larval Drosophila. We argue that the simplicity of the larval chemosensory system, combined with the experimental accessibility of Drosophila on the genetic, electrophysiological, cellular, and behavioral level, makes this system suitable for an integrated understanding of chemosensation and chemosensory learning.
Collapse
Affiliation(s)
- Bertram Gerber
- Universität Würzburg, Biozentrum, Am Hubland, Lehrstuhl für Genetik und Neurobiologie, D-97074 Würzburg, Germany.
| | | |
Collapse
|
|
36
|
Gu Y, Luo T, Yang J, Zhang D, Dai M, Jian W, Zheng S, Zhou W, Zhou W, Wu Y, Liu Y, Liu Y, Li J, Xie X, Li G, Luo M. The -822G/A polymorphism in the promoter region of the MAP4K5 gene is associated with reduced risk of type 2 diabetes in Chinese Hans from Shanghai. J Hum Genet 2006; 51:605-10. [PMID: 16699725 DOI: 10.1007/s10038-006-0402-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2006] [Accepted: 03/09/2006] [Indexed: 12/30/2022]
Abstract
MAP4K5 (mitogen-activated protein kinase kinase kinase kinase 5), an early component of MAP kinase signal cascades was shown to activate Jun kinase in mammalian cells. The association between SNPs of MAP4K5 and type 2 diabetes (T2DM) was investigated due to the known relationship of the JNK pathway with T2DM. A total of 1,399 cases were included in the study. Oral glucose tolerance test (OGTT) and insulin release test (IRT) were performed, and blood DNA samples were extracted and genotyped on the MAP4K5 -822G/A site. These cases were subdivided into central-obesity and nonobesity groups, based upon their individual waist circumference. Allele-specific real-time PCR was employed for genotyping. No difference was found between the two groups in the distribution of three genotypes on MAP4K5 -822G/A. In the central-obesity group, fewer diabetic patients (38.9%) were present in the AA genotype group than the GG/GA group (58.5%, P=0.024). Glucose levels after 30 and 60 min of 75 g glucose tolerance, area under the curve for glucose, and insulin secretion indexes were lower (P<0.05) in AA than those in GG/GA genotype group in the central-obesity cases. Other variables did not show significant differences between the two groups. In the Han population from Shanghai, the AA genotype of MAP4K5 -822G/A in central-obesity cases appears less likely to develop diabetes compared with the other genotypes. Therefore, the G allele may be a factor that does not protect central-obesity cases from developing into diabetes.
Collapse
Affiliation(s)
- Yanyun Gu
- School of Medicine, Ruijin Hospital, Endocrine and Metabolic Disease Deparment, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai JiaoTong University, People's Republic China.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Tang RQ, Zhao XZ, Shi YY, Tang W, Gu NF, Feng GY, Xing YL, Zhu SM, Sang H, Liang PJ, He L. Family-based association study of Epsin 4 and Schizophrenia. Mol Psychiatry 2006; 11:395-9. [PMID: 16402136 DOI: 10.1038/sj.mp.4001780] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Recently, Pimm et al. identified Epsin 4 on chromosome 5q33 as a susceptibility gene for schizophrenia in the British population, based on linkage and association evidence. In Pimm's case-control study, both the single polymorphisms and the individual haplotypes at the 5' end of the gene showed genetic association with schizophrenia. Here, we report the first study evaluating the relevance of Epsin 4 and schizophrenia outside the British population. Markers showing positive results in the original work as well as two additional polymorphisms were genotyped in 308 Han Chinese family trios. Transmission disequilibrium analysis was used to test for association of single-locus markers and multi-locus haplotypes with schizophrenia. Although no individual marker was significant at the P=0.05 level, the haplotypes detected in our samples, different from those previously reported, showed strong evidence of association (most significant global P=0.0021). Our results indicate the presence of a locus near the 5' end of Epsin 4 conferring susceptibility to the disease and provide further support for Epsin 4 as an important potential contributor to genetic risk in schizophrenia.
Collapse
Affiliation(s)
- R Q Tang
- Bio-X Life Science Research Center, Shanghai Jiao Tong University, Shanghai, China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Yang YF, Qin W, Shugart YY, He G, Liu XM, Zhou J, Zhao XZ, Chen Q, La YJ, Xu YF, Li XW, Gu NF, Feng GY, Song H, Wang P, He L. Possible association of the MAG locus with schizophrenia in a Chinese Han cohort of family trios. Schizophr Res 2005; 75:11-19. [PMID: 15820319 DOI: 10.1016/j.schres.2004.11.013] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2004] [Revised: 11/19/2004] [Accepted: 11/22/2004] [Indexed: 12/15/2022]
Abstract
Neurotransmitter-based hypotheses have so far led to only moderate success in predicting new pathogenetic findings in etiology of schizophrenia. On the other hand, the more recent oligodendroglia hypotheses of this disorder have been supported by an increasing body of evidence. For example, the expression level of the myelin associated glycoprotein (MAG) gene has been shown to be significantly lower in schizophrenia patient groups compared to control groups. Such an effect might be a result of genetic variations of the MAG gene. In order to test this hypothesis, we genotyped four markers within the MAG locus in 413 trios sample of the Han Chinese using allele-specific PCR. None of the four markers revealed noticeable allelic significance. However, the four-marker and two-marker haplotypes covering components rs720309 and rs720308 were observed to be significantly associated with schizophrenia (P < 0.0001) in this study. In addition, we identified one common risk haplotype TA (rs720309-rs720308, present in 78.5% of the general population) that showed increased evidence of overtransmission from parents to affected offspring (P = 0.0001). The results demonstrated MAG might play a role in genetic susceptibility to schizophrenia. Furthermore, our finding of a possible association between the MAG locus and schizophrenia is in agreement with the hypotheses of oligodendrltic and myelination dysfunction.
Collapse
Affiliation(s)
- Y F Yang
- Bio-X Life Science Research Center, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, PR China
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|