title: PGC-1α provides a transcriptional framework for synchronous neurotransmitter release from parvalbumin-positive interneurons.
abstract: Accumulating evidence strongly implicates the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in the pathophysiology of multiple neurological disorders, but the downstream gene targets of PGC-1α in the brain have remained enigmatic. Previous data demonstrate that PGC-1α is primarily concentrated in inhibitory neurons and that PGC-1α is required for the expression of the interneuron-specific Ca(2+)-binding protein parvalbumin (PV) throughout the cortex. To identify other possible transcriptional targets of PGC-1α in neural tissue, we conducted a microarray on neuroblastoma cells overexpressing PGC-1α, 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-1α. We observed bidirectional regulation of novel PGC-1α-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 O subunit (Atp5o), phytanol-CoA-2hydroxylase (Phyh), and ATP synthase mitrochondrial F1 complex α subunit 1 (Atp5a1)] functions. The neuron-specific genes Syt2, Cplx1, and Nefh were developmentally upregulated in an expression pattern consistent with that of PGC-1α and were expressed in cortical interneurons. Conditional deletion of PGC-1α 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-1α is required for normal PV-positive interneuron function and that loss of PGC-1α in this interneuron subpopulation could contribute to cortical dysfunction in disease states.
authors.affiliation: Departments of Psychiatry and Behavioral Neurobiology.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Lucas
authors.affiliation: Departments of Psychiatry and Behavioral Neurobiology.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Dougherty
authors.affiliation: Departments of Psychiatry and Behavioral Neurobiology.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: McMeekin
authors.affiliation: Departments of Psychiatry and Behavioral Neurobiology.
authors.forename: Courtney S
authors.initials: CS
authors.lastname: Reid
authors.affiliation: Neurobiology, and.
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Dobrunz
authors.affiliation: Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: West
authors.affiliation: Neurobiology, and.
authors.forename: John J
authors.initials: JJ
authors.lastname: Hablitz
authors.affiliation: Departments of Psychiatry and Behavioral Neurobiology, rcowell@uab.edu.
authors.forename: Rita M
authors.identifier: http://orcid.org/0000-0001-5814-9412
authors.initials: RM
authors.lastname: Cowell
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D007395:Interneurons / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010320:Parvalbumins / Q000096:biosynthesis*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D010320:Parvalbumins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid
keywords: Barnes maze; Huntington disease; cortical development; ppargc1a; schizophrenia; strontium