| 1 | Genomics 2002 Apr 79: 560-72 |
|---|---|
| PMID | 11944989 |
| Title | An integrated, functionally annotated gene map of the DXS8026-ELK1 interval on human Xp11.3-Xp11.23: potential hotspot for neurogenetic disorders. |
| Abstract | Human chromosome Xp11.3-Xp11.23 encompasses the map location for a growing number of diseases with a genetic basis or genetic component. These include several eye disorders, syndromic and nonsyndromic forms of X-linked mental retardation (XLMR), X-linked neuromuscular diseases and susceptibility loci for schizophrenia, type 1 diabetes, and Graves' disease. We have constructed an approximately 2.7-Mb high-resolution physical map extending from DXS8026 to ELK1, corresponding to a genetic distance of approximately 5.5 cM. A combination of chromosome walking and sequence-tagged site (STS)-content mapping resulted in an integrated framework and transcript map, precisely positioning 10 polymorphic microsatellites (one of which is novel), 16 ESTs, and 12 known genes (RP2, PCTK1, UHX1, UBE1, RBM10, ZNF157, SYN1, ARAF1, TIMP1, PFC, ELK1, UXT). The composite map is currently anchored with 89 STSs to give an average resolution of approximately 1 STS every 30 kb. By a combination of EST database searches and in silico detection of UniGene clusters within genomic sequence generated from this template map, we have mapped several novel genes within this interval: a Na+/H+ exchanger (SLC9A7), at least two zincfinger transcription factors (KIAA0215 and Hs.68318), carbohydrate sulfotransferase-7 (CHST7), regucalcin (RGN), inactivation-escape-1 (INE1), the human ortholog of mouse neuronal protein 15.6, and four putative novel genes. Further genomic analysis enabled annotation of the sequence interval with 20 predicted pseudogenes and 21 UniGene clusters of unknown function. The combined PAC/BAC transcript map and YAC scaffold presented here clarifies previously conflicting data for markers and genes within the Xp11.3-Xp11.23 interval and provides a powerful integrated resource for functional characterization of this clonally unstable, yet gene-rich and clinically significant region of proximal Xp. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Synapse 2012 Nov 66: 979-83 |
| PMID | 22807112 |
| Title | The C allele of synonymous SNP (rs1142636, Asn170Asn) in SYN1 is a risk factor for the susceptibility of Korean female schizophrenia. |
| Abstract | The aim of this study was to investigate the association between the exonic single nucleotide polymorphisms (SNPs) of synapsin I (SYN1) (rs1142636, Asn170Asn, Xp11.23) and SYN2 (rs2289708, 3'-untranslated region, 3p25) in schizopherenia. Two hundred eighty six schizophrenia patients and 304 control subjects were recruited. SNPs with a know heterozygosity and minor allele frequency (MAF) > 0.1 in Asian populations were selected and genotyped by direct sequencing. The allelic frequencies of rs1142636 (SYN1) were associated with schizophrenia (P < 0.05), respectively. The allelic frequency of rs1142636 in all subjects was associated with schizophrenia [P = 0.000059, OR = 2.17 (95% CI = 1.47-3.18)]. The C allele frequency of rs1142636 was higher in schizophrenia (20.8%) than that in controls (10.8%). In the analysis of gender, the allelic frequency of rs1142636 was also strongly associated with female schizophrenia [P = 0.0001, OR = 2.65 (95% CI = 1.61-4.36)], but not with male schizophrenia. The C allele frequency of rs1142636 was higher in female schizophrenia (22.2%) than that in female controls (9.7%). The rs2289708 SNP (SYN2) did not show any association between schizophrenia and controls. These results suggest that the C allele of a synonymous SNP (rs1142636, Asn170Asn, Xp11.23) in SYN1 may be a risk factor for the susceptibility of Koreran female schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Int. J. Neuropsychopharmacol. 2013 Mar 16: 289-99 |
| PMID | 22571925 |
| Title | H3K4 tri-methylation in synapsin genes leads to different expression patterns in bipolar disorder and major depression. |
| 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. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Behav. Brain Res. 2013 Aug 251: 65-74 |
| PMID | 23280234 |
| Title | Autism-related behavioral abnormalities in synapsin knockout mice. |
| Abstract | Several synaptic genes predisposing to autism-spectrum disorder (ASD) have been identified. Nonsense and missense mutations in the SYN1 gene encoding for Synapsin I have been identified in families segregating for idiopathic epilepsy and ASD and genetic mapping analyses have identified variations in the SYN2 gene as significantly contributing to epilepsy predisposition. Synapsins (Syn I/II/III) are a multigene family of synaptic vesicle-associated phosphoproteins playing multiple roles in synaptic development, transmission and plasticity. Lack of SynI and/or SynII triggers a strong epileptic phenotype in mice associated with mild cognitive impairments that are also present in the non-epileptic SynIII(-/-) mice. SynII(-/-) and SynIII(-/-) mice also display schizophrenia-like traits, suggesting that Syns could be involved in the regulation of social behavior. Here, we studied social interaction and novelty, social recognition and social dominance, social transmission of food preference and social memory in groups of male SynI(-/-), SynII(-/-) and SynIII(-/-) mice before and after the appearance of the epileptic phenotype and compared their performances with control mice. We found that deletion of Syn isoforms widely impairs social behaviors and repetitive behaviors, resulting in ASD-related phenotypes. SynI or SynIII deletion altered social behavior, whereas SynII deletion extensively impaired various aspects of social behavior and memory, altered exploration of a novel environment and increased self-grooming. Social impairments of SynI(-/-) and SynII(-/-) mice were evident also before the onset of seizures. The results demonstrate an involvement of Syns in generation of the behavioral traits of ASD and identify Syn knockout mice as a useful experimental model of ASD and epilepsy. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Psychoneuroendocrinology 2015 Feb 52: 43-58 |
| PMID | 25459892 |
| Title | A role for synapsin in FKBP51 modulation of stress responsiveness: Convergent evidence from animal and human studies. |
| Abstract | Both the molecular co-chaperone FKBP51 and the presynaptic vesicle protein synapsin (alternatively spliced from SYN1-3) are intensively discussed players in the still insufficiently explored pathobiology of psychiatric disorders such as major depression, schizophrenia and posttraumatic stress disorder (PTSD). To address their still unknown interaction, we compared the expression levels of synapsin and five other neurostructural and HPA axis related marker proteins in the prefrontal cortex (PFC) and the hippocampus of restrained-stressed and unstressed Fkbp5 knockout mice and corresponding wild-type littermates. In addition, we compared and correlated the gene expression levels of SYN1, SYN2 and FKBP5 in three different online datasets comprising expression data of human healthy subjects as well as of predominantly medicated patients with different psychiatric disorders. In summary, we found that Fkbp5 deletion, which we previously demonstrated to improve stress-coping behavior in mice, prevents the stress-induced decline in prefrontal cortical (pc), but not in hippocampal synapsin expression. Accordingly, pc, but not hippocampal, synapsin protein levels correlated positively with a more active mouse stress coping behavior. Searching for an underlying mechanism, we found evidence that deletion of Fkbp5 might prevent stress-induced pc synapsin loss, at least in part, through improvement of pc Akt kinase activity. These results, together with our finding that FKBP5 and SYN1 mRNA levels were regulated in opposite directions in the PFC of schizophrenic patients, who are known for exhibiting an altered stress-coping behavior, provide the first evidence of a role for pc synapsin in FKBP51 modulation of stress responsiveness. This role might extend to other tissues, as we found FKBP5 and SYN1 levels to correlate inversely not only in human PFC samples but also in other expression sites. The main limitation of this study is the small number of individuals included in the correlation analyses. Future studies will have to verify the here-postulated role of the FKBP51-Akt kinase-synapsin pathway in stress responsiveness. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Psychoneuroendocrinology 2015 Feb 52: 43-58 |
| PMID | 25459892 |
| Title | A role for synapsin in FKBP51 modulation of stress responsiveness: Convergent evidence from animal and human studies. |
| Abstract | Both the molecular co-chaperone FKBP51 and the presynaptic vesicle protein synapsin (alternatively spliced from SYN1-3) are intensively discussed players in the still insufficiently explored pathobiology of psychiatric disorders such as major depression, schizophrenia and posttraumatic stress disorder (PTSD). To address their still unknown interaction, we compared the expression levels of synapsin and five other neurostructural and HPA axis related marker proteins in the prefrontal cortex (PFC) and the hippocampus of restrained-stressed and unstressed Fkbp5 knockout mice and corresponding wild-type littermates. In addition, we compared and correlated the gene expression levels of SYN1, SYN2 and FKBP5 in three different online datasets comprising expression data of human healthy subjects as well as of predominantly medicated patients with different psychiatric disorders. In summary, we found that Fkbp5 deletion, which we previously demonstrated to improve stress-coping behavior in mice, prevents the stress-induced decline in prefrontal cortical (pc), but not in hippocampal synapsin expression. Accordingly, pc, but not hippocampal, synapsin protein levels correlated positively with a more active mouse stress coping behavior. Searching for an underlying mechanism, we found evidence that deletion of Fkbp5 might prevent stress-induced pc synapsin loss, at least in part, through improvement of pc Akt kinase activity. These results, together with our finding that FKBP5 and SYN1 mRNA levels were regulated in opposite directions in the PFC of schizophrenic patients, who are known for exhibiting an altered stress-coping behavior, provide the first evidence of a role for pc synapsin in FKBP51 modulation of stress responsiveness. This role might extend to other tissues, as we found FKBP5 and SYN1 levels to correlate inversely not only in human PFC samples but also in other expression sites. The main limitation of this study is the small number of individuals included in the correlation analyses. Future studies will have to verify the here-postulated role of the FKBP51-Akt kinase-synapsin pathway in stress responsiveness. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | J. Proteome Res. 2015 Jan 14: 411-21 |
| PMID | 25363195 |
| Title | A targeted multiplexed proteomic investigation identifies ketamine-induced changes in immune markers in rat serum and expression changes in protein kinases/phosphatases in rat brain. |
| Abstract | There is substantial interest in the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine in psychiatric research because it exerts acute psychotomimetic and rapid antidepressant effects in rodents and humans. Here, we investigated proteomic changes in brain and serum after acute treatment of rats with ketamine using two targeted proteomic profiling methods. Multiplex immunoassay profiling of serum identified altered levels of interleukin 4, tumor necrosis factor alpha, and fibroblast growth factor 9, suggesting a link between ketamine exposure and peripheral inflammation and growth factor dysregulation. Selected reaction monitoring mass spectrometry profiling of rat brain tissue found that proteomic changes occurred in the frontal cortex and to a greater extent in the hippocampus. This involved changes in signaling kinases and proteases such as protein kinase C beta, neurochondrin (NCDN), calcineurin, extracellular signal-regulated kinsase 1 (ERK1), and mammalian target of rapamycin (MTOR). Furthermore, altered levels were found for proteins associated with neurotransmitter metabolism (mitochondrial aspartate aminotransferase, catechol O-methyl transferase, synaptic vesicle endo-/exocytosis (vesicle fusing ATPase (NSF), synapsin 1 (SYN1), syndapin-1 (PACN1)). Consistent with previous global proteomic studies, we confirmed known changes in mitochondrial complex I, prohibitin (PHB) and neurofilament proteins (neurofilament light chain and ?-internexin (AINX)). Taken together, the proteomic changes parallel those described in human psychiatric pathology. The results will help to elucidate ketamine's mechanism of action, which will facilitate development of novel drugs for the treatment of schizophrenia and major depressive disorder. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Mol Neuropsychiatry 2015 Jul 1: 82-93 |
| PMID | 26405684 |
| Title | Olanzapine Reversed Brain Gene Expression Changes Induced by Phencyclidine Treatment in Non-Human Primates. |
| Abstract | The NMDA receptor antagonist phencyclidine (PCP) creates schizophrenia-like symptoms in normal controls. The effect of PCP on non-human primate brain gene expression was examined and compared to changes induced by olanzapine treatment. Experimental studies of PCP and antipsychotic drugs have direct relevance to understanding the patho-physiology and treatment of schizophrenia. Genome-wide changes in prefrontal cortex gene expression revealed alterations of 146 transcripts in the PCP treatment group compared to vehicle controls. Dysregulated genes were enriched in identified classes implicated in neurological and genetic disorders, including schizophrenia genes from the Psychiatric Genomics Consortium 108 loci as well as cell death in PCP-treated primates. Canonical pathway analysis revealed a significant overrepresentation of several groups including synaptic long-term potentiation and calcium signaling. Olanzapine coadministered with PCP normalized 34% of the 146 PCP-induced probe set expression changes, and a network of 17 olanzapine-normalized genes was identified enriched in schizophrenia candidate genes containing RGS4, SYN1 and AKT as nodes. The results of this study support the use of PCP administration in non-human primates as a glutamatergic model of schizophrenia and suggest that a large number of PCP-induced expression differences can be reversed by olanzapine. The results of this study may be informative for identification of potential candidates for pharmacogenetics and biomarker research related to the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |