| 1 | Hum. Mol. Genet. 2004 Nov 13: 2699-708 |
|---|---|
| PMID | 15345706 |
| Title | Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. |
| Abstract | Genetic variation in dysbindin (DTNBP1: dystrobrevin-binding protein 1) has recently been shown to be associated with schizophrenia. The dysbindin gene is located at chromosome 6p22.3, one of the most promising susceptibility loci in schizophrenia linkage studies. We attempted to replicate this association in a Japanese sample of 670 patients with schizophrenia and 588 controls. We found a nominally significant association with schizophrenia for four single nucleotide polymorphisms and stronger evidence for association in a multi-marker haplotype analysis (P = 0.00028). We then explored functions of dysbindin protein in primary cortical neuronal culture. Overexpression of dysbindin induced the expression of two pre-synaptic proteins, SNAP25 and synapsin I, and increased extracellular basal glutamate levels and release of glutamate evoked by high potassium. Conversely, knockdown of endogenous dysbindin protein by small interfering RNA (siRNA) resulted in the reduction of pre-synaptic protein expression and glutamate release, suggesting that dysbindin might influence exocytotic glutamate release via upregulation of the molecules in pre-synaptic machinery. The overexpression of dysbindin increased phosphorylation of Akt protein and protected cortical neurons against neuronal death due to serum deprivation and these effects were blocked by LY294002, a phosphatidylinositol 3-kinase (PI3-kinase) inhibitor. SiRNA-mediated silencing of dysbindin protein diminished Akt phosphorylation and facilitated neuronal death induced by serum deprivation, suggesting that dysbindin promotes neuronal viability through PI3-kinase-Akt signaling. Genetic variants associated with impairments of these functions of dysbindin could play an important role in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Pharmacogenomics 2006 Sep 7: 863-87 |
| PMID | 16981847 |
| Title | Genetics of antipsychotic treatment emergent weight gain in schizophrenia. |
| Abstract | Classic and modern antipsychotics can induce substantial weight gain causing diabetes, lipid abnormalities and psychological distress. Treatment emergent weight gain varies within the broad class of antipsychotics; however, an individual's propensity to develop weight gain largely depends on genetic factors. The first part of this review highlights current ideas and concepts related to antipsychotic-induced weight gain, including principles on energy homeostasis. The second part summarizes genetic findings emphasizing studies published after 2003 as prior studies have been reviewed in detail elsewhere. Candidate gene studies have produced significant findings in the 5-hydroxytryptamin 2C (5HT2C) and adrenergic alpha2a (ADRalpha2a) receptor genes, as well as in the leptin, guanine nucleotide binding protein (GNB3) and synaptomal-associated protein 25kDa (SNAP25) genes. Results from genome-wide association and linkage studies point to several chromosomal regions (e.g., 12q24) and some specific genes (e.g., promelanin concentrating hormone [PMCH], polycyctic kidney and hepatic disease 1 [PKHD1], peptidylglycine alpha-amidating monooxygenase [PAM]). However, more efforts are needed before risk prediction and personalized medicine can be made available for antipsychotic-induced weight gain. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Neuroreport 2006 May 17: 779-83 |
| PMID | 16708014 |
| Title | Neonatal exposure to MK801 induces structural reorganization of the central nervous system. |
| Abstract | schizophrenia, a progressive disorder displaying widespread pathological changes, is associated with the loss of glutamatergic function and selective loss of cytoskeletal proteins, such as MAP2, in regions severely affected by this disease. As schizophrenia is associated with perinatal brain trauma, we monitored changes in several functionally different proteins following injury-promoting MK801 blockade of N-methyl-D-aspartate receptors in neonatal rats. Within the somatosensory cortex, MK801 triggered robust, caspase-3-dependent apoptotic injury, reduced expression of cytoskeletal proteins MAP2 and tau, and increased synapse associated protein SNAP25. Thus, both neuronal injury and loss of structural elements important for successful cell-cell contact may reorganize brain circuitry, which at later ages could promote similar behavioral changes observed in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Biochem. Biophys. Res. Commun. 2006 Jun 345: 904-9 |
| PMID | 16701550 |
| Title | Hyperactivation of midbrain dopaminergic system in schizophrenia could be attributed to the down-regulation of dysbindin. |
| Abstract | Extraordinal activation of nigrostriatal and mesolimbic dopaminergic systems (midbrain dopaminergic system) is thought to be one of the most important etiologies for schizophrenia, though the reason why unusual hyperactivation of the dopaminergic system occurs in the schizophrenic brain is quite obscure. Dysbindin, one of the most susceptible genes for schizophrenia, has been reported to be reduced in the schizophrenic brain. In situ hybridization analysis showed the mRNA expression of dysbindin in the mouse substantia nigra. Furthermore, suppression of dysbindin expression in PC12 cells resulted in an increase of the expression of SNAP25, which plays an important role in neurotransmitter release, and increased the release of dopamine. On the other hand, up-regulation of dysbindin expression in PC12 cells showed a tendency to decrease the expression of SNAP25. These data suggest that dysbindin might regulate the dopamine release of the dopaminergic system via modulation of the expression of SNAP25. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Biochem. Biophys. Res. Commun. 2006 Jun 345: 904-9 |
| PMID | 16701550 |
| Title | Hyperactivation of midbrain dopaminergic system in schizophrenia could be attributed to the down-regulation of dysbindin. |
| Abstract | Extraordinal activation of nigrostriatal and mesolimbic dopaminergic systems (midbrain dopaminergic system) is thought to be one of the most important etiologies for schizophrenia, though the reason why unusual hyperactivation of the dopaminergic system occurs in the schizophrenic brain is quite obscure. Dysbindin, one of the most susceptible genes for schizophrenia, has been reported to be reduced in the schizophrenic brain. In situ hybridization analysis showed the mRNA expression of dysbindin in the mouse substantia nigra. Furthermore, suppression of dysbindin expression in PC12 cells resulted in an increase of the expression of SNAP25, which plays an important role in neurotransmitter release, and increased the release of dopamine. On the other hand, up-regulation of dysbindin expression in PC12 cells showed a tendency to decrease the expression of SNAP25. These data suggest that dysbindin might regulate the dopamine release of the dopaminergic system via modulation of the expression of SNAP25. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Schizophr. Res. 2008 Dec 106: 218-28 |
| PMID | 18774265 |
| Title | Dysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia. |
| Abstract | schizophrenia (SCZ) is a complex trait with a high heritability. The DTNBP1 gene (encoding dysbindin) is one of the leading susceptible genes of SCZ. This risk gene has been reported to be associated with clinical symptoms such as negative symptoms and cognitive deficits. Although reduction of dysbindin expression in schizophrenic brain tissue has been reported, how this contributes to its symptomatology remains uncertain. The sandy (sdy) mouse, which harbors a spontaneously occurring deletion in the Dtnbp1 gene and expresses no dysbindin protein, provides a unique tool to study the role of dysbindin in SCZ. Our recent findings reveal that the sdy mice exhibit specific defects of neurosecretion and synaptic morphology in hippocampal neurons. We here further described that sdy manifested schizophrenia-like behaviors such as social withdrawal and cognitive deficits. In sdy hippocampus, the steady-state level of snapin (a SNAP25-binding protein and a synaptic priming regulator) was reduced due to loss of dysbindin. We further characterized that a 30-residue peptide in dysbindin (90-119 amino acids) mediated the interaction with snapin. Our results suggest that the destabilization of snapin in sdy mice may lead to abnormal neurotransmission and therefore abnormal behaviors. This further defines the sdy mutant as a potential model in schizophrenia research. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Schizophr. Res. 2008 Dec 106: 218-28 |
| PMID | 18774265 |
| Title | Dysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia. |
| Abstract | schizophrenia (SCZ) is a complex trait with a high heritability. The DTNBP1 gene (encoding dysbindin) is one of the leading susceptible genes of SCZ. This risk gene has been reported to be associated with clinical symptoms such as negative symptoms and cognitive deficits. Although reduction of dysbindin expression in schizophrenic brain tissue has been reported, how this contributes to its symptomatology remains uncertain. The sandy (sdy) mouse, which harbors a spontaneously occurring deletion in the Dtnbp1 gene and expresses no dysbindin protein, provides a unique tool to study the role of dysbindin in SCZ. Our recent findings reveal that the sdy mice exhibit specific defects of neurosecretion and synaptic morphology in hippocampal neurons. We here further described that sdy manifested schizophrenia-like behaviors such as social withdrawal and cognitive deficits. In sdy hippocampus, the steady-state level of snapin (a SNAP25-binding protein and a synaptic priming regulator) was reduced due to loss of dysbindin. We further characterized that a 30-residue peptide in dysbindin (90-119 amino acids) mediated the interaction with snapin. Our results suggest that the destabilization of snapin in sdy mice may lead to abnormal neurotransmission and therefore abnormal behaviors. This further defines the sdy mutant as a potential model in schizophrenia research. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Oct 147B: 1327-31 |
| PMID | 18512733 |
| Title | No association between tagging SNPs of SNARE complex genes (STX1A, VAMP2 and SNAP25) and schizophrenia in a Japanese population. |
| Abstract | Abnormalities in neural connections and the neurotransmitter system appear to be involved in the pathophysiology of schizophrenia. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, which consists of Syntaxin1A, vesicle-associated membrane protein 2 (VAMP2) and synaptosomal-associated protein 25 kDa (SNAP25), plays an important role in the neurotransmitter system, and is therefore an attractive place to search for candidate genes for schizophrenia. We conducted a two-stage genetic association analysis of Syntaxin1A (STX1A), VAMP2 and SNAP25 genes with schizophrenia (first-set screening samples: 377 cases and 377 controls, second-set confirmation samples: 657 cases and 527 controls). Based on the linkage disequilibrium, 40 SNPs (STX1A, 8 SNPs; VAMP2, 3 SNPs; SNAP25, 29 SNPs) were selected as 'tagging SNPs'. Only nominally significant associations of an SNP (rs12626080) and haplotype (rs363014 and rs12626080) in SNAP25 were detected in the first-set screening scan. To validate this significance, we carried out a replication analysis of these SNP and haplotype associations in second-set samples with a denser set of markers (including five additional SNPs). However, these associations could not be confirmed in the second-set analysis. These results suggest that the SNARE complex-related genes do not play a major role in susceptibility to schizophrenia in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Oct 150B: 893-9 |
| PMID | 19132710 |
| Title | Evidence that putative ADHD low risk alleles at SNAP25 may increase the risk of schizophrenia. |
| Abstract | Synaptosomal Associated Protein 25 kDa (SNAP25) has been implicated in the pathogenesis of schizophrenia by numerous neuropathological studies and genetic variation at SNAP25 has been reported to be associated with ADHD. Expression levels of the putative schizophrenia susceptibility gene DTNBP1 has been shown to influence the levels of SNAP25 in vitro. We undertook directed mutation screening of SNAP25 in UK schizophrenic cases followed by direct association analysis of all variants identified and identified known exonic SNPs that showed evidence for association (rs3746544 P = 0.004 OR = 1.26, rs8636 P = 0.003 OR = 1.27), although these SNPs are highly correlated (r(2) > 0.99). We additionally genotyped a further 31 tag SNPs spanning the SNAP25 locus and identified several independent SNPs that were nominally associated with schizophrenia (strongest association at rs3787283, P = 0.006, OR = 1.25) however, due to the number of tests performed no SNP met experiment-wise significance (minimum permuted P-value = 0.1). Post hoc analysis revealed that the SNPs nominally associated with schizophrenia (rs3787283, rs3746544) were the same as those previously demonstrated to be associated with ADHD but with the opposite alleles, allowing the intriguing hypothesis that genetic variation at SNAP25 may be differentially associated with both schizophrenia and ADHD. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Oct 150B: 893-9 |
| PMID | 19132710 |
| Title | Evidence that putative ADHD low risk alleles at SNAP25 may increase the risk of schizophrenia. |
| Abstract | Synaptosomal Associated Protein 25 kDa (SNAP25) has been implicated in the pathogenesis of schizophrenia by numerous neuropathological studies and genetic variation at SNAP25 has been reported to be associated with ADHD. Expression levels of the putative schizophrenia susceptibility gene DTNBP1 has been shown to influence the levels of SNAP25 in vitro. We undertook directed mutation screening of SNAP25 in UK schizophrenic cases followed by direct association analysis of all variants identified and identified known exonic SNPs that showed evidence for association (rs3746544 P = 0.004 OR = 1.26, rs8636 P = 0.003 OR = 1.27), although these SNPs are highly correlated (r(2) > 0.99). We additionally genotyped a further 31 tag SNPs spanning the SNAP25 locus and identified several independent SNPs that were nominally associated with schizophrenia (strongest association at rs3787283, P = 0.006, OR = 1.25) however, due to the number of tests performed no SNP met experiment-wise significance (minimum permuted P-value = 0.1). Post hoc analysis revealed that the SNPs nominally associated with schizophrenia (rs3787283, rs3746544) were the same as those previously demonstrated to be associated with ADHD but with the opposite alleles, allowing the intriguing hypothesis that genetic variation at SNAP25 may be differentially associated with both schizophrenia and ADHD. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Mar 153B: 663-74 |
| PMID | 19806613 |
| Title | Association study of SNAP25 and schizophrenia in Irish family and case-control samples. |
| Abstract | SNAP25 occurs on chromosome 20p12.2, which has been linked to schizophrenia in some samples, and recently linked to latent classes of psychotic illness in our sample. SNAP25 is crucial to synaptic functioning, may be involved in axonal growth and dendritic sprouting, and its expression may be decreased in schizophrenia. We genotyped 18 haplotype-tagging SNPs in SNAP25 in a sample of 270 Irish high-density families. Single marker and haplotype analyses were performed in FBAT and PDT. We adjusted for multiple testing by computing q values. Association was followed up in an independent sample of 657 cases and 411 controls. We tested for allelic effects on the clinical phenotype by using the method of sequential addition and 5 factor-derived scores of the OPCRIT. Nine of 18 SNPs had P values <0.05 in either FBAT or PDT for one or more definitions of illness. Several two-marker haplotypes were also associated. Subjects inheriting the risk alleles of the most significantly associated two-marker haplotype were likely to have higher levels of hallucinations and delusions. The most significantly associated marker, rs6039820, was observed to perturb 12 transcription-factor binding sites in in silico analyses. An attempt to replicate association findings in the case-control sample resulted in no SNPs being significantly associated. We observed robust association in both single marker and haplotype-based analyses between SNAP25 and schizophrenia in an Irish family sample. Although we failed to replicate this in an independent sample, this gene should be further tested in other samples. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | J. Neurosci. 2012 Jun 32: 8716-24 |
| PMID | 22723711 |
| Title | Snapin is critical for presynaptic homeostatic plasticity. |
| Abstract | The molecular mechanisms underlying the homeostatic modulation of presynaptic neurotransmitter release are largely unknown. We have previously used an electrophysiology-based forward genetic screen to assess the function of >400 neuronally expressed genes for a role in the homeostatic control of synaptic transmission at the neuromuscular junction of Drosophila melanogaster. This screen identified a critical function for dysbindin, a gene linked to schizophrenia in humans (Dickman and Davis, 2009). Biochemical studies in other systems have shown that Snapin interacts with Dysbindin, prompting us to test whether Snapin might be involved in the mechanisms of synaptic homeostasis. Here, we demonstrate that loss of snapin blocks the homeostatic modulation of presynaptic vesicle release following inhibition of postsynaptic glutamate receptors. This is true for both the rapid induction of synaptic homeostasis induced by pharmacological inhibition of postsynaptic glutamate receptors, and the long-term expression of synaptic homeostasis induced by the genetic deletion of the muscle-specific GluRIIA glutamate receptor subunit. Loss of snapin does not alter baseline synaptic transmission, synapse morphology, synapse growth, or the number or density of active zones, indicating that the block of synaptic homeostasis is not a secondary consequence of impaired synapse development. Additional genetic evidence suggests that snapin functions in concert with dysbindin to modulate vesicle release and possibly homeostatic plasticity. Finally, we provide genetic evidence that the interaction of Snapin with SNAP25, a component of the SNARE complex, is also involved in synaptic homeostasis. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | Psychiatry Res 2013 Jan 205: 7-12 |
| PMID | 22940547 |
| Title | Preliminary evidence for association between schizophrenia and polymorphisms in the regulatory Regions of the ADRA2A, DRD3 and SNAP-25 Genes. |
| Abstract | The results of linkage and candidate gene association studies have led to a range of hypotheses about the pathogenesis of schizophrenia. We limited our study to polymorphisms in candidate genes involved in dopaminergic and noradrenergic systems, and in the 25KDa synaptosomal-associated protein (SNAP-25) gene that is related to neurotransmitter exocytosis. Eight single nucleotide polymorphisms (SNPs) in regulating or coding regions of genes for the alpha-2A adrenergic receptor (ADRA2A), dopamine receptors D1 and D3 (DRD1 and DRD3), dopamine ?-hydroxylase (DBH) and SNAP-25 were genotyped in male patients with schizophrenia (n=192) and in healthy controls (n=213). These polymorphisms were previously associated with schizophrenia. The allelic association between schizophrenia and ADRA2A rs1800544 polymorphism, SNAP-25 rs1503112 polymorphism, and DRD3 rs6280 polymorphism was found in our study. However, only observations for rs1503112 survived correction for multiple testing. Association was also evaluated by considering the polymorphisms as interactions; in this case, a likelihood ratio test (LRT) revealed evidence for association with schizophrenia in four polymorphism combinations: two DRD3*SNAP-25 combinations (rs6280*rs3746544 and rs6280*rs3746544, P=0.02), one ADRA2A*SNAP25 combination (rs1800544*rs3746544) and one ADRA2A*DBH combination (rs1800544*rs2519152). Our results are in agreement with the previously proposed role of DNA polymorphisms involved in dopaminergic, noradrenergic and synaptic functions in the pathogenesis of schizophrenia. Further relevant studies including larger sample size and more markers are needed to confirm our results. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 14 | Exp. Eye Res. 2013 Nov 116: 1-8 |
| PMID | 23954924 |
| Title | Developmental expression of dysbindin in Muller cells of rat retina. |
| Abstract | Dysbindin, the product of the DTNBP1 gene, was identified by yeast two hybrid assay as a binding partner of dystrobrevin, a cytosolic component of the dystrophin protein complex. Although its functional role has not yet been completely elucidated, the finding that dysbindin assembles into the biogenesis of lysosome related organelles complex 1 (BLOC-1) suggests that it participates in intracellular trafficking and biogenesis of organelles and vesicles. Dysbindin is ubiquitous and in brain is expressed primarily in neurons. Variations at the dysbindin gene have been associated with increased risk for schizophrenia. As anomalies in retinal function have been reported in patients suffering from neuropsychiatric disorders, we investigated the expression of dysbindin in the retina. Our results show that differentially regulated dysbindin isoforms are expressed in rat retina during postnatal maturation. Interestingly, we found that dysbindin is mainly localized in Müller cells. The identification of dysbindin in glial cells may open new perspectives for a better understanding of the functional involvement of this protein in visual alterations associated to neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 15 | Neuroreport 2013 Nov 24: 928-33 |
| PMID | 24045778 |
| Title | Expression of presynaptic markers in a neurodevelopmental animal model with relevance to schizophrenia. |
| Abstract | Administration of N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) to rat pups at postnatal day (PND) 7, 9, and 11 [neonatal PCP (neoPCP) model] induces cognitive deficits similar to those observed in schizophrenia. Expression of presynaptic SNARE protein, synaptosomal-associated protein of 25 kDa (SNAP25), has been shown to be downregulated in postmortem brains from patients with schizophrenia. The present study was designed to investigate the long-term effects of neoPCP administration on expression of presynaptic markers altered in schizophrenia. Using radioactive in-situ hybridization, the expression of SNAP25 was measured in the prefrontal cortex and the hippocampal formation (CA1, CA3, CA4, and dentate gyrus) at PND 29 and 80 in neoPCP and control rats. As a secondary presynaptic marker, the expressional level of synaptophysin was also measured in the same areas. Stereological estimation of the number of neurons and volume was used to exclude potential bias in cell numbers. A significant reduction in the expression of SNAP25 in the hippocampal CA4 region was observed in adult neoPCP rats (PND 80, P<0.01), but not in preadolescent rats (PND 29), indicating a late developmental manifestation of a presynaptic pathology. The number of neurons and volume of the CA4 region showed no change in PCP rats compared with the controls. Furthermore, expression of another presynaptic marker, synaptophysin, remained unaffected by the PCP treatment. These findings indicate that perinatal PCP injections induce a delayed presynaptic impact on the vesicle fusion machinery in a brain region important for cognitive processes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 16 | Brain Res. 2013 Sep 1532: 85-98 |
| PMID | 23939223 |
| Title | Gene-environment interactions affect long-term depression (LTD) through changes in dopamine receptor affinity in Snap25 deficient mice. |
| Abstract | Genes and environmental conditions interact in the development of cognitive capacities and each plays an important role in neuropsychiatric disorders such as attention deficit/hyperactivity disorder (ADHD) and schizophrenia. Multiple studies have indicated that the gene for the SNARE protein SNAP-25 is a candidate susceptibility gene for ADHD, as well as schizophrenia, while maternal smoking is a candidate environmental risk factor for ADHD. We utilized mice heterozygous for a SNAP25 null allele and deficient in SNAP-25 expression to model genetic effects in combination with prenatal exposure to nicotine to explore genetic and environmental interactions in synaptic plasticity and behavior. We show that SNAP-25 deficient mice exposed to prenatal nicotine exhibit hyperactivity and deficits in social interaction. Using a high frequency stimulus electrophysiological paradigm for long-term depression (LTD) induction, we examined the roles of dopaminergic D2 receptors (D2Rs) and cannabinoid CB1 receptors (CB1Rs), both critical for LTD induction in the striatum. We found that prenatal exposure to nicotine in SNAP25 heterozygote null mice produced a deficit in the D2R-dependent induction of LTD, although CB1R regulation of plasticity was not impaired. We also show that prenatal nicotine exposure altered the affinity and/or receptor coupling of D2Rs, but not the number of these receptors in heterozygote null SNAP25 mutants. These results refine the observations made in the coloboma mouse mutant, a proposed mouse model of ADHD, and illustrate how gene×environmental influences can interact to perturb neural functions that regulate behavior. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 17 | Biomed Rep 2014 Sep 2: 729-736 |
| PMID | 25054019 |
| Title | Meta-analyses of 10 polymorphisms associated with the risk of schizophrenia. |
| Abstract | schizophrenia (SCZ) is a severe complex psychiatric disorder that generates problems for the associated family and society and causes disability with regards to work for patients. The aim of the present study was to assess the contribution of 10 genetic polymorphisms to SCZ susceptibility. Meta-analyses were conducted using the data without a limitation for time or language. A total of 27 studies with 7 genes and 10 polymorphisms were selected for the meta-analyses. Two polymorphisms were found to be significantly associated with SCZ. SNAP25 rs3746544 was shown to increase the SCZ risk by 18% [P=0.01; odds ratio (OR), 1.18; 95% confidence interval (CI), 1.05-1.34] and GRIK3 rs6691840 was found to increase the risk by 30% (P=0.008; OR, 1.30; 95% CI, 1.07-1.58). Significant results were found under the dominant (P=0.001; OR, 1.36; 95% CI, 1.13-1.65) and additive (P=0.02; OR, 1.45; 95% CI, 1.06-1.98) model for the SNAP25 rs3746544 polymorphism and under the additive model for the GRIK3 rs6691840 polymorphism (P=0.03; OR, 1.73; 95% CI, 1.04-2.85). There were no significant results observed for the other eight polymorphisms, which were CCKAR rs1800857, CHRNA7 rs904952, CHRNA7 rs6494223, CHRNA7 rs2337506, DBH Ins>Del, FEZ1 rs559668, FEZ1 rs597570 and GCLM rs2301022. In conclusion, the present meta-analyses indicated that the SNAP25 rs3746544 and GRIK3 rs6691840 polymorphisms were risk factors of SCZ, which may provide valuable information for the clinical diagnosis of SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 18 | Cereb. Cortex 2014 Feb 24: 364-76 |
| PMID | 23064108 |
| Title | Epileptiform activity and cognitive deficits in SNAP-25(+/-) mice are normalized by antiepileptic drugs. |
| Abstract | Synaptosomal-associated protein of 25 kDa (SNAP-25) is a protein that participates in the regulation of synaptic vesicle exocytosis through the formation of the soluble NSF attachment protein receptor complex and modulates voltage-gated calcium channels activity. The SNAP25 gene has been associated with schizophrenia, attention deficit hyperactivity disorder, and bipolar disorder, and lower levels of SNAP-25 have been described in patients with schizophrenia. We used SNAP-25 heterozygous (SNAP-25(+/-)) mice to investigate at which extent the reduction of the protein levels affects neuronal network function and mouse behavior. As interactions of genotype with the specific laboratory conditions may impact behavioral results, the study was performed through a multilaboratory study in which behavioral tests were replicated in at least 2 of 3 distinct European laboratories. Reductions of SNAP-25 levels were associated with a moderate hyperactivity, which disappeared in the adult animals, and with impaired associative learning and memory. Electroencephalographic recordings revealed the occurrence of frequent spikes, suggesting a diffuse network hyperexcitability. Consistently, SNAP-25(+/-) mice displayed higher susceptibility to kainate-induced seizures, paralleled by degeneration of hilar neurons. Notably, both EEG profile and cognitive defects were improved by antiepileptic drugs. These results indicate that reduction of SNAP-25 expression is associated to generation of epileptiform discharges and cognitive dysfunctions, which can be effectively treated by antiepileptic drugs. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 19 | Biol. Psychiatry 2015 Sep 78: 361-73 |
| PMID | 25662103 |
| Title | Increased SNARE Protein-Protein Interactions in Orbitofrontal and Anterior Cingulate Cortices in Schizophrenia. |
| Abstract | Synaptic dysfunction in schizophrenia may be associated with abnormal expression or function of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (syntaxin, synaptosomal-associated protein 25 [SNAP25], vesicle-associated membrane protein [VAMP]) forming the molecular complex underlying neurosecretion. The impact of such abnormalities on efficient SNARE heterotrimer formation is poorly understood. We investigated putative SNARE dysfunction, along with possible roles for the SNARE binding partners Munc18-1, complexins (Cplx) 1/2, and synaptotagmin in brains from autopsies of individuals with and without schizophrenia. Postmortem samples were obtained from orbitofrontal cortex (OFC) and/or anterior cingulate cortex from two separate cohorts (n = 15 + 15 schizophrenia cases, n = 13 + 15 control subjects). SNARE interactions were studied by immunoprecipitation and one- or two-dimensional blue native polyacrylamide gel electrophoresis (BN-PAGE). In the first cohort, syntaxin, Munc18-1, and Cplx1, but not VAMP, Cplx2, or synaptotagmin, were twofold enriched in SNAP25 immunoprecipitated products from schizophrenia OFC in the absence of any alterations in total tissue homogenate levels of these proteins. In BN-PAGE, the SNARE heterotrimer was identified as a 150-kDa complex, increased in schizophrenia samples from cohort 1 (OFC: +45%; anterior cingulate cortex: +44%) and cohort 2 (OFC: +40%), with lower 70-kDa SNAP25-VAMP dimer (-37%) in the OFC. Upregulated 200-kDa SNARE-Cplx1 (+65%) and downregulated 550-kDa Cplx1-containing oligomers (-24%) in schizophrenia OFC were identified by BN-PAGE. These findings were not explained by postmortem interval, antipsychotic medication, or other potentially confounding variables. The findings support the hypothesis of upregulated SNARE complex formation in schizophrenia OFC, possibly favored by enhanced affinity for Munc18-1 and/or Cplx1. These alterations offer new therapeutic targets for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 20 | J Clin Psychiatry 2015 Jan 76: e76-82 |
| PMID | 25650683 |
| Title | SNAP25 is associated with schizophrenia and major depressive disorder in the Han Chinese population. |
| Abstract | Synaptosomal-associated protein of 25 kDa (SNAP25) is a member of the soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) protein complex, which plays essential roles in the modulation of different voltage-gated calcium channels and neurotransmitter release. Many previous studies have reported the SNAP25 gene to be significantly associated with attention-deficit/hyperactivity disorder (ADHD). Recently, shared genetic variants have been demonstrated in 5 major psychiatric disorders, including schizophrenia, major depressive disorder, bipolar disorder, autism spectrum disorders, and ADHD. However, no compelling, convincing evidence has suggested an association between SNAP25 and schizophrenia or major depressive disorder. Thus, we investigated the association between SNAP25 and both schizophrenia and major depressive disorder in the Han Chinese population. We performed a large-scale case-control study to test the association between SNAP25 and 2 major mental disorders, schizophrenia (DSM-IV criteria) and major depressive disorder (DSM-IV criteria), in the Han Chinese population. Seven single-nucleotide polymorphisms (SNPs) were genotyped in 1,330 schizophrenia patients, 1,045 major depressive disorder patients, and 1,520 healthy controls of Han Chinese origin. Two SNPs, rs3787283 and rs3746544, were found to be associated with both schizophrenia (rs3746544, adjusted P = .00257) and major depressive disorder (rs3746544, adjusted P = .0485; rs3787283, adjusted P = .00387) in this study. The AG haplotype consisting of rs3787283 and rs3746544 was also significantly associated with both schizophrenia and major depressive disorder (schizophrenia: adjusted P = .0126; major depressive disorder: adjusted P = .000580). Additionally, we carried out a meta-analysis of the current data and published association results and further confirmed the association between rs3746544 and schizophrenia (Pmeta = .002, ORmeta = 1.213 [95% CI, 1.077-1.367]). Our results indicated that SNPs in SNAP25 represented a common risk factor of both schizophrenia and major depressive disorder in the Han Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 21 | Schizophr Bull 2016 May -1: -1 |
| PMID | 27217270 |
| Title | Pharmacogenetic Associations of Antipsychotic Drug-Related Weight Gain: A Systematic Review and Meta-analysis. |
| Abstract | Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (?7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naïve youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples (n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2-20, n = 81-2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ADRA2A], Adrenoceptor Beta 3 [ADRB3], Brain-Derived Neurotrophic Factor [BDNF], Dopamine Receptor D2 [DRD2], Guanine Nucleotide Binding Protein [GNB3], 5-Hydroxytryptamine (Serotonin) Receptor 2C [HTR2C], Insulin-induced gene 2 [INSIG2], Melanocortin-4 Receptor [MC4R], and Synaptosomal-associated protein, 25kDa [SNAP25]) were significantly associated with antipsychotic-related weight gain (P-values < .05-.001). SNPs in ADRA2A, DRD2, HTR2C, and MC4R had the largest effect sizes (Hedges' g's = 0.30-0.80, ORs = 1.47-1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1-2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 22 | Behav. Brain Res. 2016 Jan 296: 393-400 |
| PMID | 26300453 |
| Title | Different attentional abilities among inbred mice strains using virtual object recognition task (VORT): SNAP25?/? mice as a model of attentional deficit. |
| Abstract | Autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), schizophrenia, Alzheimer's and Parkinson's disease are characterized by attentional deficits. In the present study we first applied the virtual object recognition test (VORT), where 3D objects were replaced with highly discriminated geometrical shapes and presented on two 3.5-inch widescreen displays, in different inbred mice strains (C57BL/6N, DBA/2J, BALB/cJ), in comparison with the standard object recognition test (NOR). In both NOR and VORT, there was a progressive decay of performance in terms of reduced discrimination index from 5 min to 72 h of inter-trial delay in all strains. However, BALB/cJ inbred mice showed a better long lasting performance than C57BL/6N and DBA/2J, when tested in NOR. In VORT, BALB/cJ showed the best performance. Total exploration time was always higher in BALB/cJ than C57BL/6N and DBA/2J mice. C57BL/6N were less explorative strain than DBA/2J and BALB/cJ mice. When VORT was applied to SNAP-25(+/-) mice, an impairment in both NOR and VORT was shown. However, when moving shapes were applied, these heterozygous mice improved their performance, suggesting that the introduction of motion is a strong cue that makes the task more valuable to study attention deficits. Taken together, these data indicate that VORT provides a useful and rapid tool to identify the attentional deficit in different inbred strains and genetically modified mice, enhancing the value of psychiatric mouse models. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 23 | J Neural Transm (Vienna) 2016 Feb -1: -1 |
| PMID | 26856328 |
| Title | SNARE complex in developmental psychiatry: neurotransmitter exocytosis and beyond. |
| Abstract | Multiple biological processes throughout development require intracellular vesicular trafficking, where the SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors) complex plays a major role. The core proteins forming the SNARE complex are SNAP-25 (synaptosomal-associated protein 25), VAMP (vesicle-associated membrane protein) and Syntaxins, besides its regulatory proteins, such as Synaptotagmin. Genes encoding these proteins (SNAP25, VAMP1, VAMP2, STX1A, SYT1 and SYT2) have been studied in relation to psychiatric disorders susceptibility. Here, we review physiological aspects of SNARE complex and genetic association results reported for attention deficit hyperactivity disorder, both in children and adults, autism spectrum disorders, major depressive disorder, bipolar disorder and schizophrenia. Moreover, we included findings from expression, pharmacogenetics and animal model studies regarding these clinical phenotypes. The overall scenario depicted here suggests that the SNARE complex may exert distinct roles throughout development, with age-specific effects of genetic variants in psychiatric disorders. Such perspective should be considered in future studies regarding SNARE complex genes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 24 | Schizophr. Res. 2016 Mar -1: -1 |
| PMID | 26971072 |
| Title | Quantitative mass spectrometry reveals changes in SNAP-25 isoforms in schizophrenia. |
| Abstract | SNAP-25 and syntaxin are presynaptic terminal SNARE proteins altered in amount and function in schizophrenia. In the ventral caudate, we observed 32% lower SNAP-25 and 26% lower syntaxin, but greater interaction between the two proteins using an in vitro assay. SNAP-25 has two isoforms, SNAP-25A and B, differing by only 9 amino acids, but with different effects on neurotransmission. A quantitative mass spectrometry assay was developed to measure total SNAP-25, and proportions of SNAP-25A and B. The assay had a good linear range (50- to 150-fold) and coefficient of variation (4.5%). We studied ventral caudate samples from patients with schizophrenia (n=15) previously reported to have lower total SNAP-25 than controls (n=13). We confirmed 27% lower total SNAP-25 in schizophrenia, and observed 31% lower SNAP-25A (P=0.002) with 20% lower SNAP-25B amounts (P=0.10). Lower SNAP-25A amount correlated with greater SNAP-25-syntaxin protein-protein interactions (r=-0.41, P=0.03); the level of SNAP-25B did not. Administration of haloperidol or clozapine to rats did not mimic the changes found in schizophrenia. The findings suggest that lower levels of SNAP-25 in schizophrenia may represent a greater effect of the illness on the SNAP-25A isoform. This in turn could contribute to the greater interaction between SNAP25 and syntaxin, and possibly disturb neurotransmission in the illness. |
| SCZ Keywords | schizophrenia, schizophrenic |