| 1 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Oct 147B: 1327-31 |
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| 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 |
| 2 | Eur Arch Psychiatry Clin Neurosci 2010 Nov 260 Suppl 2: S81-9 |
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| PMID | 20945070 |
| Title | Differential expression of presynaptic genes in a rat model of postnatal hypoxia: relevance to schizophrenia. |
| Abstract | Obstetric complications play a role in the pathophysiology of schizophrenia. However, the biological consequences during neurodevelopment until adulthood are unknown. Microarrays have been used for expression profiling in four brain regions of a rat model of neonatal hypoxia as a common factor of obstetric complications. Animals were repeatedly exposed to chronic hypoxia from postnatal (PD) day 4 through day 8 and killed at the age of 150 days. Additional groups of rats were treated with clozapine from PD 120-150. Self-spotted chips containing 340 cDNAs related to the glutamate system ("glutamate chips") were used. The data show differential (up and down) regulations of numerous genes in frontal (FR), temporal (TE) and parietal cortex (PAR), and in caudate putamen (CPU), but evidently many more genes are upregulated in frontal and temporal cortex, whereas in parietal cortex the majority of genes are downregulated. Because of their primary presynaptic occurrence, five differentially expressed genes (CPX1, NPY, NRXN1, SNAP-25, and STX1A) have been selected for comparisons with clozapine-treated animals by qRT-PCR. Complexin 1 is upregulated in FR and TE cortex but unchanged in PAR by hypoxic treatment. Clozapine downregulates it in FR but upregulates it in PAR cortex. Similarly, syntaxin 1A was upregulated in FR, but downregulated in TE and unchanged in PAR cortex, whereas clozapine downregulated it in FR but upregulated it in PAR cortex. Hence, hypoxia alters gene expression regionally specific, which is in agreement with reports on differentially expressed presynaptic genes in schizophrenia. Chronic clozapine treatment may contribute to normalize synaptic connectivity. |
| SCZ Keywords | schizophrenia |
| 3 | Int. J. Dev. Neurosci. 2011 May 29: 225-36 |
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| PMID | 20888897 |
| Title | Molecular evidence that cortical synaptic growth predominates during the first decade of life in humans. |
| Abstract | Theories concerning the pathology of human neurodevelopmental disorders that emerge in adolescence, such as schizophrenia, often hypothesize that there may be a failure of normal cortical synaptic loss or pruning. However, direct evidence that synaptic regression is a major developmental event in the adolescent human cortex is limited. Furthermore, developmental work in rodents suggested that synaptic regression in adolescence is not a major feature of cortical development. Thus, we set out to determine when and to what extent molecular markers of synaptic terminals [synaptophysin (SYP), SNAP-25, syntaxin1A (STX1A), and vesicle-associated membrane protein 1 (VAMP1)] are reduced during postnatal human life spanning from 1 month to 45 years (n = 69) using several different quantitative methods, microarray, qPCR and immunoblotting. We found little evidence for a consistent decrease in synaptic-related molecular markers at any time point, but instead found clear patterns of gradual increases in expression of some presynaptic markers with postnatal age (including SNAP-25, VAMP1 and complexin 1 (CPLX1) mRNAs and 6/6 presynaptic proteins evaluated). A measure of synaptic plasticity [growth-associated protein of 43 kDa (GAP-43)] was elevated in neonates, and continued robust expression throughout life. Since CPLX1 protein is enriched in inhibitory terminals we also tested if the protein product of complexin 2 (CPLX2), which is enriched in excitatory neurons, is more specifically reduced in development. In contrast to CPLX1, which showed a steady increase in both mRNA and protein levels during postnatal development (both r > 0.58, p < 0.001), CPLX2 mRNA decreased from infants to toddlers (r = -0.56, p < 0.001), while CPLX2 protein showed a steady increase until young adulthood (r = 0.55, p < 0.001). Furthermore, we found that indices of the dendrites [microtubule associated protein 2 (MAP2)] and spines (spinophilin and postsynaptic density protein of 95 kDa (PSD95)] showed some evidence of reduction over time at the mRNA level but the opposite pattern, of a developmental increase, was found for PSD95 and spinophilin protein levels. Taken together, the postnatal changes in molecular components of synapses supports the notion that growth and strengthening of synaptic elements is a major developmental event occurring in the frontal cortex throughout childhood and that maintenance of steady state levels of synapse-associated molecules may predominate during human adolescence. |
| SCZ Keywords | schizophrenia |
| 4 | J Neural Transm (Vienna) 2016 Feb -1: -1 |
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| 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 |