Analysis of Synapsin III –196 Promoter Mutation in Schizophrenia and Bipolar Disorder

Lachman, Herbert M.; Stopková, Pavla; Papolos, Demitri F.; Pedrosa, Erika; Margolis, Benjamin; Aghalar, Maryam Rafael; Saito, Takuya

doi:10.1159/000091720

Cited by 21 publications

(13 citation statements)

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“…A growing body of evidence suggests that disorders like schizophrenia, bipolar disorder and ASD which show genetic overlap [97] involve synaptic abnormalities that predispose individuals to these conditions. Mutations affecting a number of synaptic proteins have been observed in schizophrenia, bipolar disorder and ASD [98]–[103]. GluD1 is developmentally expressed and has been shown to affect presynaptic differentiation and synapse formation in in vitro systems [8].…”

Section: Discussionmentioning

confidence: 99%

Deletion of Glutamate Delta-1 Receptor in Mouse Leads to Aberrant Emotional and Social Behaviors

et al. 2012

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The delta family of ionotropic glutamate receptors consists of glutamate δ1 (GluD1) and glutamate δ2 (GluD2) receptors. While the role of GluD2 in the regulation of cerebellar physiology is well understood, the function of GluD1 in the central nervous system remains elusive. We demonstrate for the first time that deletion of GluD1 leads to abnormal emotional and social behaviors. We found that GluD1 knockout mice (GluD1 KO) were hyperactive, manifested lower anxiety-like behavior, depression-like behavior in a forced swim test and robust aggression in the resident-intruder test. Chronic lithium rescued the depression-like behavior in GluD1 KO. GluD1 KO mice also manifested deficits in social interaction. In the sociability test, GluD1 KO mice spent more time interacting with an inanimate object compared to a conspecific mouse. D-Cycloserine (DCS) administration was able to rescue social interaction deficits observed in GluD1 KO mice. At a molecular level synaptoneurosome preparations revealed lower GluA1 and GluA2 subunit expression in the prefrontal cortex and higher GluA1, GluK2 and PSD95 expression in the amygdala of GluD1 KO. Moreover, DCS normalized the lower GluA1 expression in prefrontal cortex of GluD1 KO. We propose that deletion of GluD1 leads to aberrant circuitry in prefrontal cortex and amygdala owing to its potential role in presynaptic differentiation and synapse formation. Furthermore, these findings are in agreement with the human genetic studies suggesting a strong association of GRID1 gene with several neuropsychiatric disorders including schizophrenia, bipolar disorder, autism spectrum disorders and major depressive disorder.

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Section: Discussionmentioning

confidence: 99%

Deletion of Glutamate Delta-1 Receptor in Mouse Leads to Aberrant Emotional and Social Behaviors

et al. 2012

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“…The SNP rs133945 is potentially functional, because an ATTT motif is located at position -196 that resembles the octamer sequence recognized by members of the POU family of transcription factors [123]. Indeed, the G-allele of this SNP has consistently resulted in greater binding to brain proteins than the A-allele, suggesting that this polymorphism has an effect on DNA-protein complexes [123]. The functional relevance of rs133946 has not been investigated.…”

Section: Neuropsychiatric Disordersmentioning

confidence: 99%

“…Interestingly, no striking differences in the frequencies of these SNPs were observed in schizophrenia [113, 123] or bipolar disorder [123], although there were trends towards significance in some ethnic samples, suggesting that the studies were underpowered. However, there were significant differences in protein-DNA interactions using protein extracts from postmortem brains of individuals with bipolar disorder and synthetic DNA corresponding to alleles of rs133945 [123].…”

Section: Neuropsychiatric Disordersmentioning

confidence: 99%

“…However, there were significant differences in protein-DNA interactions using protein extracts from postmortem brains of individuals with bipolar disorder and synthetic DNA corresponding to alleles of rs133945 [123]. These results suggest that additional variables (e.g.. composition of protein extracts) should be considered when investigating the functional relevance of a polymorphism.…”

Section: Neuropsychiatric Disordersmentioning

confidence: 99%

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Synapsin III: Role in neuronal plasticity and disease

Porton

Wetsel

Kao

2011

Seminars in Cell & Developmental Biology

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Synapsin III was discovered in 1998, more than two decades after the first two synapsins (synapsins I and II) were identified. Although the biology of synapsin III is not as well understood as synapsins I and II, this gene is emerging as an important factor in the regulation of the early stages of neurodevelopment and dopaminergic neurotransmission, and in certain neuropsychiatric illnesses. Molecular genetic and clinical studies of synapsin III have determined that its neurodevelopmental effects are exerted at the levels of neurogenesis and axonogenesis. In vitro voltammetry studies have shown that synapsin III can control dopamine release in the striatum. Since dopaminergic dysfunction is implicated in many neuropsychiatric conditions, one may anticipate that polymorphisms in synapsin III can exert pervasive effects, especially since it is localized to extrasynaptic sites. Indeed, mutations in this gene have been identified in individuals diagnosed with schizophrenia, bipolar disorder and multiple sclerosis. These and other findings indicate that the roles of synapsin III differ significantly from those of synapsins I and II. Here, we focus on the unique roles of the newest synapsin, and where relevant, compare and contrast these with the actions of synapsins I and II.

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“…There are several association studies of SYN3 and schizophrenia in different populations, including those of Asian, European and African ancestry, but most of the results are negative, and positive findings are not consistent across studies [8;12;13;17–20;22]. For example, Porton and colleagues found that a rare, missense polymorphism, S470N, appeared more frequently in European individuals with schizophrenia (5%) than in controls (0.9%) (p=0.0048)[19].…”

Section: Introductionmentioning

confidence: 99%

Association and expression study of synapsin III and schizophrenia

Chen

Che

Wang

et al. 2009

Neuroscience Letters

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The synapsin III gene, SYN3, which belongs to the family of synaptic vesicle-associated proteins, has been implicated in the modulation of neurotransmitter release and in synaptogenesis, suggesting a potential role in several neuropsychiatric diseases. The human SYN3 gene is located on chromosome 22q12-13, a candidate region implicated in previous linkage studies of schizophrenia. However, association studies of SYN3 and schizophrenia have produced inconsistent results. In this study, four SYN3 SNPs (rs133945(−631c>g), rs133946 (−196g>a), rs9862 and rs1056484) were tested in three sets of totally 3759 samples that comprise 655 affected subjects and 626 controls in the Irish CaseControl Study of Schizophrenia (ICCSS), 1350 samples incorporating 273 pedigrees in the Irish Study of High Density Schizophrenia Families (ISHDSF), and 564 unrelated schizophrenia patients and 564 healthy individuals in a Chinese case-control sample. The expression levels of SYN3 in schizophrenic patients and unaffected controls were compared using postmortem brain cDNAs provided by the Stanley Medical Research Institute (SMRI). There was no significant association in either the Irish or Chinese case-control samples, nor in the combined samples. Consistent with this finding, we did not find any significant difference in allele or haplotype frequencies when we used the pedigree disequilibrium test to analyze the Irish family sample. In the expression studies, no significant difference (p=0.507) was observed between patients and controls. Both the association studies and expression studies didn't support a major role for SYN3 in the susceptibility of schizophrenia in Irish and Chinese populations. 5Corresponding author: Qi Chen, qchen2@uchicago.edu, Tel: 804-248-5087. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Vawter and colleagues reported that, compared to controls, there were reductions in synapsin IIa and IIIa proteins in the hippocampus of schizophrenia patients (p=0.034) [24]. Furthermore, Porton and colleagues found that synapsin III protein levels were reduced in patients in the prefrontal cortex, an area believed to be the major locus of dysfunction in schizophrenia [20; 24]. NIH Public AccessIn this study, we tested for an association between four SYN3 SNPs and schizophrenia in more than 3750 samples, including three Irish sets of 655 cases and 626 controls, an Irish family sample of 273 pedigrees totally about 1350 subjects, and 564 Chinese unrelated patients with schizophrenia and 564 Chinese controls. We also measured the mRNA levels in postmortem brain from schizophrenia ...

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Analysis of Synapsin III –196 Promoter Mutation in Schizophrenia and Bipolar Disorder

Cited by 21 publications

References 68 publications

Deletion of Glutamate Delta-1 Receptor in Mouse Leads to Aberrant Emotional and Social Behaviors

Deletion of Glutamate Delta-1 Receptor in Mouse Leads to Aberrant Emotional and Social Behaviors

Synapsin III: Role in neuronal plasticity and disease

Association and expression study of synapsin III and schizophrenia

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