| 1 | J. Neurosci. 2014 Oct 34: 14375-87 |
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| PMID | 25339750 |
| Title | PGC-1? provides a transcriptional framework for synchronous neurotransmitter release from parvalbumin-positive interneurons. |
| Abstract | Accumulating evidence strongly implicates the transcriptional coactivator peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?) in the pathophysiology of multiple neurological disorders, but the downstream gene targets of PGC-1? in the brain have remained enigmatic. Previous data demonstrate that PGC-1? is primarily concentrated in inhibitory neurons and that PGC-1? is required for the expression of the interneuron-specific Ca(2+)-binding protein parvalbumin (PV) throughout the cortex. To identify other possible transcriptional targets of PGC-1? in neural tissue, we conducted a microarray on neuroblastoma cells overexpressing PGC-1?, mined results for genes with physiological relevance to interneurons, and measured cortical gene and protein expression of these genes in mice with underexpression and overexpression of PGC-1?. We observed bidirectional regulation of novel PGC-1?-dependent transcripts spanning synaptic [synaptotagmin 2 (Syt2) and complexin 1 (Cplx1)], structural [neurofilament heavy chain (NEFH)], and metabolic [neutral cholesterol ester hydrolase 1 (Nceh1), adenylate kinase 1 (Ak1), inositol polyphosphate 5-phosphatase J (Inpp5j), ATP synthase mitochondrial F1 complex O subunit (Atp5o), phytanol-CoA-2hydroxylase (Phyh), and ATP synthase mitrochondrial F1 complex ? subunit 1 (Atp5a1)] functions. The neuron-specific genes Syt2, Cplx1, and NEFH were developmentally upregulated in an expression pattern consistent with that of PGC-1? and were expressed in cortical interneurons. Conditional deletion of PGC-1? in PV-positive neurons significantly decreased cortical transcript expression of these genes, promoted asynchronous GABA release, and impaired long-term memory. Collectively, these data demonstrate that PGC-1? is required for normal PV-positive interneuron function and that loss of PGC-1? in this interneuron subpopulation could contribute to cortical dysfunction in disease states. |
| SCZ Keywords | schizophrenia |
| 2 | Schizophr Bull 2015 Dec -1: -1 |
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| PMID | 26683626 |
| Title | Cortical PGC-1?-Dependent Transcripts are Reduced in Postmortem Tissue From Patients With Schizophrenia. |
| Abstract | The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1?) has been linked to multiple neurological and psychiatric disorders including schizophrenia, but its involvement in the pathophysiology of these disorders is unclear. Experiments in mice have revealed a set of developmentally-regulated cortical PGC-1?-dependent transcripts involved in calcium buffering (parvalbumin, PV), synchronous neurotransmitter release (synaptotagmin 2, Syt2; complexin 1, Cplx1) and axonal integrity (neurofilamaent heavy chain, NEFH). We measured the mRNA expression of PGC-1? and these transcripts in postmortem cortical tissue from control and schizophrenia patients and found a reduction in PGC-1?-dependent transcripts without a change in PGC-1?. While control subjects with high PGC-1? expression exhibited high PV and NEFH expression, schizophrenia subjects with high PGC-1? expression did not, suggesting dissociation between PGC-1? expression and these targets in schizophrenia. Unbiased analyses of the promoter regions for PGC-1?-dependent transcripts revealed enrichment of binding sites for the PGC-1?-interacting transcription factor nuclear respiratory factor 1 (NRF-1). NRF-1 mRNA expression was reduced in schizophrenia, and its transcript levels predicted that of PGC-1?-dependent targets in schizophrenia. Interestingly, the positive correlation between PGC-1? and PV, Syt2, or Cplx1 expression was lost in schizophrenia patients with low NRF-1 expression, suggesting that NRF-1 is a critical predictor of these genes in disease. These data suggest that schizophrenia involves a disruption in PGC-1? and/or NRF-1-associated transcriptional programs in the cortex and that approaches to enhance the activity of PGC-1? or transcriptional regulators like NRF-1 should be considered with the goal of restoring normal gene programs and improving cortical function. |
| SCZ Keywords | schizophrenia |
| 3 | Schizophr. Res. 2016 May -1: -1 |
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| PMID | 27236410 |
| Title | Altered CSNK1E, FABP4 and NEFH protein levels in the dorsolateral prefrontal cortex in schizophrenia. |
| Abstract | schizophrenia constitutes a complex disease. Negative and cognitive symptoms are enduring and debilitating components of the disorder, highly associated to disability and burden. Disrupted neurotransmission circuits in dorsolateral prefrontal cortex (DLPFC) have been related to these symptoms. To identify candidates altered in schizophrenia, we performed a pilot proteomic analysis on postmortem human DLPFC tissue from patients with schizophrenia (n=4) and control (n=4) subjects in a pool design using differential isotope peptide labelling followed by liquid chromatography tandem mass spectrometry (LC-MS/MS). We quantified 1315 proteins with two or more unique peptides, 116 of which showed altered changes. Of these altered proteins, we selected four with potential roles on cell signaling, neuronal development and synapse functioning for further validation: casein kinase I isoform epsilon (CSNK1E), fatty acid-binding protein 4 (FABP4), neurofilament triplet H protein (NEFH), and retinal dehydrogenase 1 (ALDH1A1). Immunoblot validation confirmed our proteomic findings of these proteins being decreased in abundance in the schizophrenia samples. Additionally, we conducted immunoblot validation of these candidates on an independent sample cohort comprising 23 patients with chronic schizophrenia and 23 matched controls. In this second cohort, CSNK1E, FABP4 and NEFH were reduced in the schizophrenia group while ALDH1A1 did not significantly change. This study provides evidence indicating these proteins are decreased in schizophrenia: CSNK1E, involved in circadian molecular clock signaling, FABP4 with possible implication in synapse functioning, and NEFH, important for cytoarchitecture organization. Hence, these findings suggest the possible implication of these proteins in the cognitive and/or negative symptoms in schizophrenia. |
| SCZ Keywords | schizophrenia |