| 1 | Proc. Natl. Acad. Sci. U.S.A. 2007 Jun 104: 10164-9 |
|---|
| PMID | 17553960 |
| Title | Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars. |
| Abstract | GABAergic dysfunction is present in the hippocampus in schizophrenia (SZ) and bipolar disorder (BD). The trisynaptic pathway was "deconstructed" into various layers of sectors CA3/2 and CA1 and gene expression profiling performed. Network association analysis was used to uncover genes that may be related to regulation of glutamate decarboxylase 67 (GAD(67)), a marker for this system that has been found by many studies to show decreased expression in SZs and BDs. The most striking change was a down-regulation of GAD(67) in the stratum oriens (SO) of CA2/3 in both groups; CA1 only showed changes in the SO of schizophrenics. The network generated for GAD(67) contained 25 genes involved in the regulation of kainate receptors, TGF-beta and Wnt signaling, as well as transcription factors involved in cell growth and differentiation. In SZs, IL-1beta, (GRIK2/3), TGF-beta2, TGF-betaR1, histone deacetylase 1 (HDAC1), death associated protein (DAXX), and cyclin D2 (CCND2) were all significantly up-regulated, whereas in BDs, PAX5, Runx2, LEF1, TLE1, and CCND2 were significantly down-regulated. In the SO of CA1 of BDs, where GAD67 showed no expression change, TGF-beta and Wnt signaling genes were all up-regulated, but other transcription factors showed no change in expression. In other layers/sectors, BDs showed no expression changes in these GAD(67) network genes. Overall, these results are consistent with the hypothesis that decreased expression of GAD(67) may be associated with an epigenetic mechanism in SZ. In BD, however, a suppression of transcription factors involved in cell differentiation may contribute to GABA dysfunction. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 2 | Proc. Natl. Acad. Sci. U.S.A. 2007 Jun 104: 10164-9 |
|---|
| PMID | 17553960 |
| Title | Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars. |
| Abstract | GABAergic dysfunction is present in the hippocampus in schizophrenia (SZ) and bipolar disorder (BD). The trisynaptic pathway was "deconstructed" into various layers of sectors CA3/2 and CA1 and gene expression profiling performed. Network association analysis was used to uncover genes that may be related to regulation of glutamate decarboxylase 67 (GAD(67)), a marker for this system that has been found by many studies to show decreased expression in SZs and BDs. The most striking change was a down-regulation of GAD(67) in the stratum oriens (SO) of CA2/3 in both groups; CA1 only showed changes in the SO of schizophrenics. The network generated for GAD(67) contained 25 genes involved in the regulation of kainate receptors, TGF-beta and Wnt signaling, as well as transcription factors involved in cell growth and differentiation. In SZs, IL-1beta, (GRIK2/3), TGF-beta2, TGF-betaR1, histone deacetylase 1 (HDAC1), death associated protein (DAXX), and cyclin D2 (CCND2) were all significantly up-regulated, whereas in BDs, PAX5, Runx2, LEF1, TLE1, and CCND2 were significantly down-regulated. In the SO of CA1 of BDs, where GAD67 showed no expression change, TGF-beta and Wnt signaling genes were all up-regulated, but other transcription factors showed no change in expression. In other layers/sectors, BDs showed no expression changes in these GAD(67) network genes. Overall, these results are consistent with the hypothesis that decreased expression of GAD(67) may be associated with an epigenetic mechanism in SZ. In BD, however, a suppression of transcription factors involved in cell differentiation may contribute to GABA dysfunction. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 3 | J. Neurochem. 2008 Apr 105: 512-23 |
|---|
| PMID | 18194215 |
| Title | SP1 regulates a human SNAP-25 gene expression. |
| Abstract | The synaptosomal-associated protein of 25 kDa (SNAP-25) is a pre-synaptic plasma membrane protein. SNAP-25 plays an important role in synaptic vesicle membrane docking and fusion, which is involved in the regulation of neurotransmitter release. SNAP-25 has been implicated in the pathogenesis of neuropsychiatric disorders including schizophrenia, attention-deficit hyperactivity disorder and Alzheimer's disease. We cloned a 1584 bp segment of the 5' flanking region of the human SNAP-25 gene. A series of nested deletions of the 5' flanking region fragment were subcloned into the pGL3-basic luciferase reporter plasmid. N2A cells were transfected with the SNAP-25 promoter constructs and luciferase activity was measured as an indication of promoter activity. We identified a 188 bp fragment containing the transcription initiation site as the minimal region necessary for promoter activity. Several putative cis-acting elements including SP1, hypoxia inducible factor (HIF), cAMP-response element binding protein, T-cell factor/lymphocyte enhancer factor 1 (TCF/LEF1), AP1 and the signal transducer and activator of transcription-6 (STAT6) are found in the 5' flanking region of SNAP-25 gene. Transcriptional activation and gel shift assays showed that the human SNAP-25 gene promoter contains functional SP1 response elements. Over-expression of SP1 increased SNAP-25 gene expression and inhibition of SP1-mediated transcriptional activation reduced SNAP-25 gene expression. These results suggest that SP1 plays an important role in regulation of the human SNAP-25 gene expression. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 4 | Neurochem. Res. 2013 Jun 38: 1144-55 |
|---|
| PMID | 23377854 |
| Title | Physiological role of ?-catenin/TCF signaling in neurons of the adult brain. |
| Abstract | Wnt/?-catenin pathway, the effectors of which are transcription factors of the LEF1/TCF family, is primarily associated with development. Strikingly, however, some of the genes of the pathway are schizophrenia susceptibility genes, and the proteins that are often mutated in neurodegenerative diseases have the ability to regulate ?-catenin levels. If impairment of this pathway indeed leads to these pathologies, then it likely plays a physiological role in the adult brain. This review provides an overview of the current knowledge on this subject. The involvement of ?-catenin and LEF1/TCF factors in adult neurogenesis, synaptic plasticity, and the function of thalamic neurons are discussed. The data are still very preliminary and often based on circumstantial or indirect evidence. Further research might help to understand the etiology of the aforementioned pathologies. |
| SCZ Keywords | schizophrenia, schizophrenics |