Localization of the transcriptional coactivator PGG-1α to GABAergic neurons during maturation of the rat brain

The transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1 alpha) can activate a number of transcription factors to regulate mitochondrial biogenesis and cell-specific responses to cold, fasting, and exercise. Recent studies indicate that PGC-1 alpha knockout mice exhibit behavioral abnormalities and progressive vacuolization in various brain regions. To investigate the roles for PGC-1a in the nervous system, we evaluated the temporal and cell-specific expression of PGC-1a in the normal developing rat brain. Western blot of whole brain homogenates with a PGC-1 alpha-specific antibody revealed that PGC-1 alpha protein was most abundant in the embryonic and early postnatal forebrain and cerebellum. Using quantitative reverse-transcriptase polymerase chain reaction (RT-PCR), we determined that PGC-1 alpha mRNA expression increased most markedly between postnatal days 3 (P3) and 14 in the cortex, striatum, and hippocampus. Immunohistochemical and immunofluorescence analyses of brain tissue indicated that while PGC-1 alpha was found in most neuronal populations from embryonic day 15 to P3, it was specifically concentrated in GABAergic populations from P3 to adulthood. Interestingly, PGC-1a colocalized with the developmentally regulated chemoattractant reelin in the cortex and hippocampus, and the survival-promoting transcription factor myocyte enhancing factor 2 was highly concentrated in GABAergic populations in the striatum. and cerebellum at times of PGC-1 alpha expression. These results implicate PGC-1a as a regulator of metabolism and/or survival in GABAergic neurons during a phase of mitochondrial and synaptic changes in the developing brain and suggest that PGC-1 alpha may be a good target for increasing metabolism in GABAergic populations in neurodevelopmental and neurodegenerative disorders.