Polymorphisms in the promoter and coding regions of the synapsin III gene. A lack of association with schizophrenia

The human synapsin III gene, located on chromosome 22q12-13, has previously been reported to indicate a susceptibility for schizophrenia. Noval rare variants (Thr136Thr in exon 3, Pro468Ser, Glu525Gln and Pro534Leu in exon 12, and 1769 G/C in the untranslated region of exon 13) were found in addition to the polymorphic variant (-196 G/A in the promoter region). No significant differences in genotypic or allelic frequencies of the -196 G/A polymorphism were found between 87 unrelated schizophrenic patients and 100 healthy controls, even when the patients were diagnostically subdivided into subtypes and course specifiers. Furthermore, allelic frequencies of the GATG repeat in intron 1 were not significantly different between the patients and the controls. These results suggest that synapsin III gene polymorphisms are not associated with schizophrenia.     

An analysis of synapsin II, a neuronal phosphoprotein, in postmortem brain tissue from alcoholic and neuropsychiatrically ill adults and medically ill children and young adults

Synapsin II (formerly known as protein III) is a synaptic vesicle-associated neuronal phosphoprotein that may be involved in the regulation of neurotransmitter release. Synapsin II was studied in postmortem brain samples from 132 individuals with various neuropsychiatric and medical diagnoses. Molecular weight variants of synapsin II were present in 73% of samples from alcoholic individuals but in only 31% of samples from non-diseased individuals, thus confirming our two previous reports of an association between synapsin II variants and alcoholism. The presence of synapsin II variants was not correlated with age or nutritional state. Synapsin II variants were also present in 56% of samples from individuals with schizophrenia and 41% of samples from individuals with Huntington's disease. Synapsin II variants were present in samples from children and young adults, consistent with the possibility that synapsin II variants may reflect a genetically inherited trait. Synapsin II variants were not found in any of 18 rodent models of alcoholism, aging, or vitamin B deficiency, suggesting that synapsin II variants may be a uniquely human trait.     

Mutational analysis of the synapsin III gene on chromosome 22q12-q13 in schizophrenia

Synapsins are a family of neuron-specific, synaptic vesicle-associated phosphoproteins that have been implicated in the modulation of neurotransmitter release. Synapsins are coded by three distinct genes for synapsin I. II, and III. The synapsin III gene is located on human chromosome 22q12-q13, where a possible schizophrenia susceptibility locus is located. Using the single strand conformation polymorphism method, we searched for variants in 13 exons and the 5'-flanking region of the synapsin III gene in schizophrenia. Three polymorphisms, -631C/G, -271T/C, and E525Q, and one rare variant, -669C >A, were identified. Case-control comparisons of these polymorphisms revealed no significant differences in the allelic and genotypic distributions between schizophrenic and control subjects. The present study did not provide evidence for an association between the synapsin III gene and schizophrenia.     

Positive association between synapsin II and schizophrenia.

BACKGROUND: Synapsin II encodes a neuron-specific phosphoprotein that selectively binds to small synaptic vesicles in the presynaptic nerve terminal. The expressions of messenger ribonucleic acid and protein of synapsin II have been reported to be significantly reduced in the brains of schizophrenia patients. The synapsin II gene is located on 3p25, a region that has been implicated to be associated with schizophrenia by genetic linkage. All these findings suggest synapsin II as a candidate gene for schizophrenia. METHODS: In this work, we studied four markers (two single nucleotide polymorphisms (SNPs): rs308963 and rs795009; and two insertion/deletion polymorphisms: rs2307981 and rs2308169) covering 144.2 kilobase pairs (kb) with an average interval of 38 kb in synapsin II in a sample of 654 schizophrenic patients and 628 normal control subjects to explore the mechanism underlying schizophrenia. RESULTS: We found significant differences in allele frequency distribution of SNP rs795009 (p =.000018, odds ratio 1.405, 95% confidence interval 1.202-1.641) between patients and control subjects. The T allele was significantly higher in patients than in control subjects. Moreover, the overall frequency of haplotype showed significant differences between patients and control subjects (p <.000001). CONCLUSIONS: This study suggests a positive association between synapsin II and schizophrenia, implying that synapsin II is involved in the etiology of schizophrenia.     

Mutation and association analysis of the 5' region of the dopamine D3 receptor gene in schizophrenia patients: identification of the Ala38Thr polymorphism and suggested association between DRD3 haplotypes and schizophrenia

Although the association between the Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) and schizophrenia has been investigated by many research groups, it is not known whether the Ser9Gly polymorphism alone or a variation in linkage disequilibrium may effect susceptibility to schizophrenia. We searched the 5' region of the DRD3 gene and found three novel polymorphisms: -712G/C, -205A/G, and Ala38Thr. The Ala38Thr polymorphism is located in the first transmembrane region and is conserved in the monkey, mouse, and rat. Case-control comparisons in 153 Japanese schizophrenia patients and 122 Japanese controls did not suggest an association between Ala38Thr and schizophrenia. However, there was a marginally significant association between the Ser9 allele of the Ser9Gly polymorphisms and schizophrenia (P = 0.02). Furthermore, there was a highly significant association between haplotypes of the -712G/C, -205A/G, and Ser9Gly polymorphisms and schizophrenia (P = 0.0007, corrected P = 0.007). These positive findings were replicated in an additional 99 Japanese schizophrenia patients and 132 controls (P = 0.04 and 0.0004, respectively). The most allelic differences of the Ser9Gly polymorphism between patient and control groups arose from the chromosome carrying specific alleles of the other three polymorphisms. This study indicates unknown variant(s) in linkage disequilibrium with the DRD3 haplotypes associated with schizophrenia.     

Behavioral effects of non-viral mediated RNA interference of synapsin II in the medial prefrontal cortex of the rat

Synapsin II is a synaptic vesicle-associated phosphoprotein that has been implicated in the pathophysiology of schizophrenia. Researchers have demonstrated reductions in synapsin II mRNA and protein in post-mortem prefrontal cortex and hippocampus samples from patients with schizophrenia. Synapsin II protein expression has been shown to be regulated by dopamine D(1) and D(2) receptor activation. Furthermore, behavioral testing of the synapsin II knockout mouse has revealed a schizophrenic-like behavioral phenotype in this mutant strain, suggesting a relationship between dysregulated and/or reduced synapsin II and schizophrenia. However, it remains unknown the specific regions of the brain of which perturbations in synapsin II play a role in the pathophysiology of this disease. The aim of this project was to evaluate animals with a selective knock-down of synapsin II in the medial prefrontal cortex through the use of siRNA technology. Two weeks after continuous infusion of synapsin II siRNAs, animals were examined for the presence of a schizophrenic-like behavioral phenotype. Our results reveal that rats with selective reductions in medial prefrontal cortical synapsin II demonstrate deficits in sensorimotor gating (prepulse inhibition), hyperlocomotion, and reduced social behavior. These results implicate a role for decreased medial prefrontal cortical synapsin II levels in the pathophysiology of schizophrenia and the mechanisms of aberrant prefrontal cortical circuitry, and suggest that increasing synapsin II levels in the medial prefrontal cortex may potentially serve as a novel therapeutic target for this devastating disorder.     

The Ser9Gly polymorphism of the dopamine D3 receptor gene and risk of schizophrenia: an association study and a large meta-analysis

Dopamine D3 receptor (DRD3) binds antipsychotic drugs and is abundant in the limbic system of the brain. It has been shown to play important roles in schizophrenia. A number of studies investigated the Ser9Gly polymorphism of the DRD3 gene to test its possible association with schizophrenia; however, the results were inconsistent. Our study aims to further evaluate the possible association between the Ser9Gly polymorphism and schizophrenia using a case-control association study within the Han Chinese population as well as a meta-analysis covering all previous studies. Our study, based on 329 schizophrenic patients and 288 controls, found no significant difference in the genotype or allele distributions of Ser9Gly polymorphism, the meta-analysis showed that the Ser9Gly polymorphism was not associated with Schizophrenia. Our study does not support the contention that the Ser9Gly polymorphism of the DRD3 gene plays a major role in schizophrenia in the Chinese population.     

Reduction of synapsin III in the prefrontal cortex of individuals with schizophrenia

We analyzed the expression of a presynaptic protein, synapsin III, in individuals with schizophrenia. Since levels of synapsin III were previously found to be significantly reduced in the hippocampus of individuals with schizophrenia, we examined another brain region believed to be a major locus of dysfunction in schizophrenia, the dorsolateral prefrontal cortex (DLPFC). Western blot analyses using tissue obtained from the Stanley Foundation Neuropathology Consortium revealed that synapsin III levels were significantly decreased in the DLPFC of individuals with schizophrenia compared to controls. These findings are consistent with growing evidence of presynaptic abnormalities and prefrontal cortical dysfunction in schizophrenia.     

Molecular analysis of synapsin I, a candidate gene for Rett syndrome

The characteristics of Rett syndrome suggest that it is an X-linked neurodegenerative disorder. Laboratory investigations to date have not revealed any metabolic abnormalities in affected individuals. Synapsin I is a neuron-specific protein thought to play a fundamental role in neuronal function. In this report we summarize the circumstantial evidence suggesting that a defect in synapsin I gene structure or expression might be involved in Rett syndrome. This evidence includes analysis of structural and functional aspects of synapsin I primary structure, characterization of synapsin I messenger RNAs, location of the synapsin I gene on the human X chromosome and preliminary analysis of synapsin I gene structure in Rett individuals.     

No association between the DRD3 Ser9Gly polymorphism and schizophrenia

OBJECTIVE: To investigate the association between a Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) and schizophrenia. METHODS: 408 schizophrenic patients and 172 control subjects were compared with regard to their DRD3 Ser9Gly genotypic and allelic frequencies. In addition, we carried out a family-based association study including 183 pedigrees (472 subjects) using the transmission disequilibrium test (TDT). RESULTS: No significant differences of genotype or homozygosity distribution were identified between patients and controls. When patients were stratified according to gender, response to treatment, age at onset, no significant differences were observed. Neither allele A (Ser), or G (Gly) were preferentially transmitted from parents to affected offspring. CONCLUSION: The hypothesis that the DRD3 Ser9Gly polymorphism plays a predisposing role in schizophrenia is not supported by this study.     

Medial prefrontal cortical synapsin II knock-down induces behavioral abnormalities in the rat: examining synapsin II in the pathophysiology of schizophrenia

Synapsin II is a synaptic vesicle-associated phosphoprotein that has been implicated in the pathophysiology of schizophrenia. Studies have demonstrated reductions in synapsin II mRNA and protein in medial prefrontal cortical post-mortem samples from patients with schizophrenia, genetic associations between synapsin II and schizophrenia, and synapsin II protein regulation by dopamine receptor activation. Collectively, this research indicates a relationship between synapsin II dysregulation and schizophrenia; however, it remains unknown whether perturbations in synapsin II play a role in the pathophysiology of this disease. The aim of this project was to evaluate animals with selective knock-down of synapsin II in the medial prefrontal cortex. After continuous infusion of synapsin II antisense sequences, animals were examined for the presence of schizophrenic-like behavioral phenotypes and assessed on the response to clinically relevant antipsychotic drugs. Our results indicate that rats with selective reductions in medial prefrontal cortical synapsin II demonstrate deficits in sensorimotor gating (prepulse inhibition), reduced social behavior, and hyperlocomotion, which are corrected by the atypical antipsychotic drug olanzapine. Additionally, synapsin II knock-down disrupts serial search efficiency. These behavioral changes are accompanied by reductions in vesicular neurotransmitter transporter protein concentrations for glutamate (VGLUT1 and VGLUT2) and GABA (VGAT), without affecting dopamine (VMAT2). These results implicate a causal role for decreased synapsin II in the medial prefrontal cortex in the pathophysiology of schizophrenia and the mechanisms of aberrant prefrontal cortical circuitry, and suggest that synapsin II may potentially serve as a novel therapeutic target for this disorder.     

Association between dopamine D3 receptor gene polymorphisms and schizophrenia in an isolate population

There are several lines of evidence implicating the dopamine D3 receptor in the pathophysiology of schizophrenia. The Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) has been the most extensively investigated DRD3 variant in connection with the disease but results have been inconclusive. Recent reports indicate that the Ser9Gly polymorphism is in linkage disequilibrium with other markers, but association studies between DRD3 haplotypes and schizophrenia have had mixed results. Genetic heterogeneity may be one of the causes of contradicting results. In order to clarify the role of DRD3 alterations in the aetiology of disease, we have investigated three D3 genetic variants (Ser9Gly, -205-G/A, -7685-G/C) in a sample of patients with schizophrenia or schizoaffective disorder (N=118) and controls (N=162) recruited from a human isolate from Navarra (Northern Spain) of Basque origin. Although no association was found between the Ser9Gly or the -205-A/G polymorphisms and disease, an excess of allele -7685-C was observed in patients (p=0.002 after correction for multiple analyses). Haplotype analysis shows the three markers to be in strong linkage disequilibrium (p<0.0001) and strongly associated with disease (p<1x 10(-5)). These results may suggest that these polymorphisms exert a combined or synergistic effect on susceptibility to schizophrenia, or are in linkage with an unknown causative factor. However, further replication in independent samples is required.     

Behavioral abnormalities in synapsin II knockout mice implicate a causal factor in schizophrenia

Recent studies on the phosphoprotein synapsin II have revealed reduced expression in postmortem medial prefrontal cortex tissues from subjects with schizophrenia, and chronic antipsychotic drug treatment has resulted in concurrent increases in synapsin II mRNA and protein levels. Collectively, this research suggests a role of synapsin II in the pathophysiology of schizophrenia; however, whether synapsin II plays a causal role in this disease process still remains unclear. Therefore, the goal of this investigation was to examine whether synapsin II knockout mice display behavioral abnormalities commonly expressed in preclinical animal models of schizophrenia, namely deficits in prepulse inhibition (PPI), decreased social behavior, and locomotor hyperactivity. Results indicate that mice with knockout of the synapsin II gene demonstrate deficits in PPI at three prepulse intensities (67, 70, and 73 dB), along with deficits in habituation to startle to a 110 dB acoustic pulse. Knockout animals also expressed decreased social behavior and increased locomotor activity when compared to wildtype and heterozygous populations. Complete knockout of the synapsin II gene was confirmed in postmortem brain tissues via immunoblotting. In conclusion, these results confirm that synapsin II knockout mice display behavioral endophenotypes similar to established preclinical animal models of schizophrenia, and lend support to the notion that abnormalities in synapsin II expression may play a causal role in the underlying pathophysiological mechanisms of schizophrenia. Synapse 63:662–672, 2009. © 2009 Wiley‐Liss, Inc.     

Early involvement of synapsin III in neural progenitor cell development in the adult hippocampus

Synapsin III is a synaptic vesicle-associated protein that is expressed in cells of the subgranular layer of the hippocampal dentate gyrus, a brain region known to sustain substantial levels of neurogenesis into adulthood. Here we tested the hypothesis that synapsin III plays a role in adult neurogenesis with synapsin III knockout and wild-type mice. Immunocytochemistry of the adult hippocampal dentate gyrus revealed that synapsin III colocalizes with markers of neural progenitor cell development (nestin, PSA-NCAM, NeuN, and Tuj1) but did not colocalize with markers of mitosis (Ki67 and PCNA). Because neurogenesis consists of a number of stages, the proliferation, survival, and differentiation of neural progenitor cells were systematically quantitated in the hippocampal dentate gyrus of adult synapsin III knockout and wild-type mice. We found a 30% decrease in proliferation and a 55% increase in survival of neural progenitor cells in synapsin III knockout mice. We also observed a 6% increase in the number of neural progenitor cells that differentiated into neurons. No difference in the volume of the dentate gyrus was observed between synapsin III knockout and wild-type mice. Collectively, our results demonstrate a novel role for synapsin III in regulating the proliferation of neural progenitor cells in the adult hippocampal dentate gyrus. These findings suggest a distinct function for this synaptic vesicle protein, in addition to its role in neurotransmission.     

多巴胺D3受体基因多态性与精神分裂症

目的:探讨沈阳地区汉族人群中多巴胺D3受体基因(DRD3)第一外显子第9密码子A→G单核苷酸置换多态性(Ser9Gly多态)与精神分裂症的关联。方法:采用聚合酶链反应-限制性内切酶片断长度多态性(PCR-RFLP)技术对70例精神分裂症患者、94名健康对照者进行基因分型鉴定。比较患者组与对照组DRD3多态性分布频率、精神分裂症早发组与非早发组基因分布频率差异,并与其他国家人群进行比较。结果:患者组与对照组之间等位基因分布无明显差异,早发组与非早发组亦未发现明显差异,而该位点等位基因分布频率与巴西、英国人群有明显差异。结论:研究人群中未发现DRD3基因Ser9Gly多态与精神分裂症存在明显关联。     

Association between the ionotropic glutamate receptor kainate3 (GRIK3) Ser310Ala polymorphism and schizophrenia in the Indian population

Various studies have been done to check the status of glutamate receptor gene in the pathogenesis of schizophrenia. The T928G (Ser310Ala) polymorphism of ionotropic glutamate receptor kainate 3 gene (GRIK3) and its positive association with schizophrenia was reported in Caucasians, whereas no association of this polymorphism with schizophrenia was shown in two other populations, Chinese and Japanese. However, no literature is available regarding the prevalence of this polymorphism and its association with schizophrenia in the Indian population. As genetic susceptibility profiles in India are often different from those of white Caucasians or Orientals, we investigated the status of Ser310Ala polymorphism of GRIK3 in 100 schizophrenic patients and 100 healthy controls in the Indian population by the PCR-RFLP (restriction fragment length polymorphism) method. A statistically significant difference in the genotype and allelic distributions (P<0.000001 and P=0.01, respectively) of Ser310Ala polymorphism was found in schizophrenics than in control, considering Ala-allele as being associated with the disease (OR=1.7, 95% CI=1.137–2.540). Our study suggests a potential role for GRIK3 for susceptibility to schizophrenia in Indian population.     

T102C polymorphisms at the 5-HT2A receptor gene in Turkish schizophrenia patients: a possible association with prognosis

BACKGROUND: Serotonergic system abnormalities have been implicated in the pathogenesis of schizophrenia. The 5-HT2A receptor gene polymorphism has long been implicated to play a role in the pathogenesis of schizophrenia. AIM: In this study, we assessed the relationship of schizophrenia and its subgroups with 5-HT2A receptor gene polymorphism, and attempted to evaluate a possible correlation between the severity and prognosis of the illness and 5-HT2A receptor gene polymorphism. METHOD: Our study comprised 141 unrelated subjects who strictly met DSM-IV criteria for schizophrenia, and 79 healthy unrelated controls, all of Turkish origin. A clinical evaluation of all patients was accomplished applying the Brief Psychiatric Rating Scale (BPRS) test. The analysis of 5-HT2A receptor gene polymorphism was performed using the polymerase chain reaction technique. RESULTS: Regarding 5-HT2A receptor gene polymorphisms, no statistically significant difference was found between schizophrenic patients and control subjects (p > 0.05). There was no significant difference between the average of BPRS points of the patients and 5-HT2A receptor gene polymorphisms (p > 0.05). Although there was no correlation between the duration of illness and polymorphism (p > 0.05), the frequency of hospitalization was found to be higher in the patients with T/C and T/T genotypes compared with the patients with C/C genotype (p < 0.05). CONCLUSION: Our findings indicate that the T102C polymorphisms of the 5-HT2A receptor gene does not play a substantial role in schizophrenia nor help evaluate susceptibility to schizophrenia. Since the 5-HT2A receptor gene polymorphism is associated with the frequency of hospitalization of the patients, it may be an indicator of prognosis in schizophrenia or help differentiate the patients who are somewhat refractory to antipsychotic treatment.     

Analysis of the fyn kinase gene in Alzheimer's disease and schizophrenia]

Reelin is a protein which plays an important role in cell construction and proliferation of neurons during the development of the central nervous system. Several lines of evidence suggest a possible role for reelin-related genes in the etiology of neurodevelopmental as well as neurodegenerative diseases. It is possible that variations in reelin-related genes (Reelin, VLDLR, FYN, CNRs, a3b1INTEGRIN, mDAB1) may be involved in the pathogenesis of schizophrenia and Alzheimer's disease. We have been conducting a systematic survey of the association of reelin-related gene polymorphisms with these disorders. Previously, we examined the association of the triplet repeats of the reelin and VLDLR gene with schizophrenia. We found no significant association of schizophrenia with the trinucleotide repeat polymorphism of the reelin nor VLDLR genes (Akahane et al. 2002). In this study, we performed an allelic association analysis in Alzheimer's disease and schizophrenia with three polymorphisms of the fyn gene reported by Ishiguro et al (2000). Diagnosis was based on DSM-IV and NINCDS-ADRDA. We found no significant differences in genotype distribution or allelic frequency between patient and control groups. Thus, it is unlikely that these polymorphisms play an important role in the pathogenesis of Alzheimer's disease or schizophrenia.     

The lymphotoxin Cys13Arg polymorphism and cognitive functioning in individuals with schizophrenia

Genetic factors that modulate the immune response have been implicated as risk factors for schizophrenia and cognitive impairment. We assessed the correlation between cognitive functioning and the LTA Cys13Arg polymorphism in 351 individuals with schizophrenia, 122 with bipolar disorder, and 160 controls. There was a significant association between cognitive functioning and the LTA Cys13Arg polymorphism within the schizophrenia (p<0.008) but not the other diagnostic groups. There was no association between cognitive functioning and the two other polymorphisms in the same gene complex. The LTA Cys13Arg polymorphism may represent a risk factor for cognitive impairment in individuals with schizophrenia.