• L J McMeekin, A F Bartley, A S Bohannon, E W Adlaf, T van Groen, S M Boas, S N Fox, P J Detloff, D K Crossman, L S Overstreet-Wadiche, J J Hablitz, L E Dobrunz, and R M Cowell.
• Department of Neuroscience, Drug Discovery Division at Southern Research, Birmingham, AL 35205, USA; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
• Neuroscience. 2020 May 21; 435: 73-94.

AbstractThe transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a critical regulator of genes involved in neuronal metabolism, neurotransmission, and morphology. Reduced PGC-1α expression has been implicated in several neurological and psychiatric disorders. An understanding of PGC-1α's roles in different cell types will help determine the functional consequences of PGC-1α dysfunction and/or deficiency in disease. Reports from our laboratory and others suggest a critical role for PGC-1α in inhibitory neurons with high metabolic demand such as fast-spiking interneurons. Here, we document a previously unrecognized role for PGC-1α in maintenance of gene expression programs for synchronous neurotransmitter release, structure, and metabolism in neocortical and hippocampal excitatory neurons. Deletion of PGC-1α from these neurons caused ambulatory hyperactivity in response to a novel environment and enhanced glutamatergic transmission in neocortex and hippocampus, along with reductions in mRNA levels from several PGC-1α neuron-specific target genes. Given the potential role for a reduction in PGC-1α expression or activity in Huntington Disease (HD), we compared reductions in transcripts found in the neocortex and hippocampus of these mice to that of an HD knock-in model; few of these transcripts were reduced in this HD model. These data provide novel insight into the function of PGC-1α in glutamatergic neurons and suggest that it is required for the regulation of structural, neurosecretory, and metabolic genes in both glutamatergic neuron and fast-spiking interneuron populations in a region-specific manner. These findings should be considered when inferring the functional relevance of changes in PGC-1α gene expression in the context of disease.Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.

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