Journal
SCHIZOPHRENIA BULLETIN
Volume 42, Issue 4, Pages 1009-1017Publisher
OXFORD UNIV PRESS
DOI: 10.1093/schbul/sbv184
Keywords
transcriptional regulation; interneuron; maturation
Categories
Funding
- National Institute of Mental Health [MH077955-05]
- National Institute of Neurological Disorders and Stroke [NS070009]
- Civitan Emerging Scholar award
- McNulty Investigator award
- UAB Center for Clinical and Translational Science from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) [UL1TR001417]
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The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1 alpha) 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 alpha-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 alpha and these transcripts in postmortem cortical tissue from control and schizophrenia patients and found a reduction in PGC-1 alpha-dependent transcripts without a change in PGC-1 alpha. While control subjects with high PGC-1 alpha expression exhibited high PV and Nefh expression, schizophrenia subjects with high PGC-1 alpha expression did not, suggesting dissociation between PGC-1 alpha expression and these targets in schizophrenia. Unbiased analyses of the promoter regions for PGC-1 alpha-dependent transcripts revealed enrichment of binding sites for the PGC-1 alpha-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 alpha-dependent targets in schizophrenia. Interestingly, the positive correlation between PGC-1 alpha 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 alpha and/ or NRF-1-associated transcriptional programs in the cortex and that approaches to enhance the activity of PGC-1 alpha or transcriptional regulators like NRF-1 should be considered with the goal of restoring normal gene programs and improving cortical function.
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