© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. The transcriptional coactivator peroxisome proliferatoractivated 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.