title: Cortical PGC-1α-Dependent Transcripts Are Reduced in Postmortem Tissue From Patients With Schizophrenia.
abstract: The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) 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-1α-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-1α and these transcripts in postmortem cortical tissue from control and schizophrenia patients and found a reduction in PGC-1α-dependent transcripts without a change in PGC-1α. While control subjects with high PGC-1α expression exhibited high PV and Nefh expression, schizophrenia subjects with high PGC-1α expression did not, suggesting dissociation between PGC-1α expression and these targets in schizophrenia. Unbiased analyses of the promoter regions for PGC-1α-dependent transcripts revealed enrichment of binding sites for the PGC-1α-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-1α-dependent targets in schizophrenia. Interestingly, the positive correlation between PGC-1α 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-1α and/or NRF-1-associated transcriptional programs in the cortex and that approaches to enhance the activity of PGC-1α or transcriptional regulators like NRF-1 should be considered with the goal of restoring normal gene programs and improving cortical function.
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL;
authors.forename: Laura J
authors.initials: LJ
authors.lastname: McMeekin
authors.affiliation: Fishberg Department of Neuroscience and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY;
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Lucas
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL;
authors.forename: James H
authors.initials: JH
authors.lastname: Meador-Woodruff
authors.affiliation: Department of Psychiatry, University of Cincinnati, Cincinnati, OH;
authors.forename: Robert E
authors.initials: RE
authors.lastname: McCullumsmith
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Hendrickson
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL;
authors.forename: Karen L
authors.initials: KL
authors.lastname: Gamble
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL; rcowell@uab.edu.
authors.forename: Rita M
authors.initials: RM
authors.lastname: Cowell
mesh_terms: D000328:Adult; D001344:Autopsy; D002540:Cerebral Cortex / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D051265:NF-E2-Related Factor 1 / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism*; D055815:Young Adult
chemical_list: D051265:NF-E2-Related Factor 1; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
keywords: interneuron; maturation; transcriptional regulation