Parvalbumin Deficiency and GABAergic Dysfunction in Mice Lacking PGC-1α

The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1 alpha(PGC-1 alpha) is a master regulator of metabolism in peripheral tissues, and it has been proposed that PGC-1 alpha plays a similar role in the brain. Recent evidence suggests that PGC-1 alpha is concentrated in GABAergic interneurons, so we investigated whether male and female PGC-1 alpha -/- mice exhibit abnormalities in interneuron gene expression and/or function. We found a striking reduction in the expression of the Ca2+-binding protein parvalbumin (PV), but not other GABAergic markers, throughout the cerebrum in PGC-1 alpha +/- and -/- mice. Furthermore, PGC-1 alpha overexpression in cell culture was sufficient to robustly induce PV expression. Consistent with a reduction in PV rather than a loss of PV-expressing interneurons, spontaneous synaptic inhibition was not altered in PGC-1 alpha -/- mice. However, evoked synaptic responses displayed less paired-pulse depression and dramatic facilitation in response to repetitive stimulation at the gamma frequency. PV transcript expression was also significantly reduced in retina and heart of PGC-1 alpha -/- animals, suggesting that PGC-1 alpha is required for proper expression of PV in multiple tissues. Together these findings indicate that PGC-1 alpha is a novel regulator of interneuron gene expression and function and a potential therapeutic target for neurological disorders associated with interneuron dysfunction.