A Role for PGC-1α in Transcription and Excitability of Neocortical and Hippocampal Excitatory Neurons

The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) is a critical regulator of genes involved in neuronal metabolism, neurotransmission, and morphology. Reduced PGC-1 alpha expression has been implicated in several neurological and psychiatric disorders. An understanding of PGC-1 alpha's roles in different cell types will help determine the functional consequences of PGC-1 alpha dysfunction and/or deficiency in disease. Reports from our laboratory and others suggest a critical role for PGC-1 alpha in inhibitory neurons with high metabolic demand such as fast-spiking interneurons. Here, we document a previously unrecognized role for PGC-1 alpha in maintenance of gene expression programs for synchronous neurotransmitter release, structure, and metabolism in neocortical and hippocampal excitatory neurons. Deletion of PGC-1 alpha 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-1 alpha neuron-specific target genes. Given the potential role for a reduction in PGC-1 alpha 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-1 alpha 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-1 alpha gene expression in the context of disease. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.