1J. Neurosci. 2014 Oct 34: 14375-87
TitlePGC-1? provides a transcriptional framework for synchronous neurotransmitter release from parvalbumin-positive interneurons.
AbstractAccumulating 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 Keywordsschizophrenia
2Schizophr Bull 2015 Dec -1: -1
TitleCortical PGC-1?-Dependent Transcripts are Reduced in Postmortem Tissue From Patients With Schizophrenia.
AbstractThe 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 Keywordsschizophrenia
3J Neural Transm (Vienna) 2016 Feb -1: -1
TitleSNARE complex in developmental psychiatry: neurotransmitter exocytosis and beyond.
AbstractMultiple 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 Keywordsschizophrenia