PGC-1α Provides a Transcriptional Framework for Synchronous Neurotransmitter Release from Parvalbumin-Positive Interneurons

Accumulating evidence strongly implicates the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) in the pathophysiology of multiple neurological disorders, but the downstream gene targets of PGC-1 alpha in the brain have remained enigmatic. Previous data demonstrate that PGC-1 alpha is primarily concentrated in inhibitory neurons and that PGC-1 alpha is required for the expression of the interneuron-specific Ca2+-binding protein parvalbumin (PV) throughout the cortex. To identify other possible transcriptional targets of PGC-1 alpha in neural tissue, we conducted a microarray on neuroblastoma cells overexpressing PGC-1 alpha, mined results for genes with physiological relevance to interneurons, and measured cortical gene and protein expression of these genes in mice with underexpression and overexpression of PGC-1 alpha. We observed bidirectional regulation of novel PGC-1 alpha-dependent transcripts spanning synaptic [synaptotagmin 2 (Syt2) and complexin 1 (Cplx1)], structural [neurofilament heavy chain (Nefh)], and metabolic [neutral cholesterol ester hydrolase 1 (Nceh1), adenylate kinase 1 (Ak1), inositol polyphosphate 5-phosphatase J (Inpp5j), ATP synthase mitochondrial F1 complex 0 subunit (Atp5o), phytanol-CoA-2hydroxylase (Phyh), and ATP synthase mitrochondrial F1 complex alpha subunit 1 (Atp5a1)] functions. The neuron-specific genes Syt2, Cplx1, and Nefh were developmentally upregulated in an expression pattern consistent with that of PGC-1 alpha and were expressed in cortical interneurons. Conditional deletion of PGC-1 alpha in PV-positive neurons significantly decreased cortical transcript expression of these genes, promoted asynchronous GABA release, and impaired long-term memory. Collectively, these data demonstrate that PGC-1 alpha is required for normal PV-positive interneuron function and that loss of PGC-1 alpha in this interneuron subpopulation could contribute to cortical dysfunction in disease states.