PV-specific loss of the transcriptional coactivator PGC-1α slows down the evolution of epileptic activity in an acute ictogenic model.

Abstract

The transcriptional coactivator, PGC-1 (peroxisome proliferator activated receptor gamma coactivator 1), plays a key role coordinating energy requirement within cells. Its importance is reflected in the growing number of psychiatric and neurological conditions that have been associated with reduced PGC-1 levels. In cortical networks, PGC-1 is required for the induction of parvalbumin (PV) expression in interneurons, and PGC-1 deficiency affects synchronous GABAergic release. It is unknown, however, how this affects cortical excitability. We show here that knocking down PGC-1 specifically in the PV-expressing cells (PGC-1PV-/-), blocks the activity-dependent regulation of the synaptic proteins, SYT2 and CPLX1. More surprisingly, this cell-class specific knock-out of PGC-1 appears to have a novel anti-epileptic effect, as assayed in brain slices bathed in 0 Mg2+ media. The rate of pre-ictal discharges developed approximately equivalently in wild-type and PGC-1PV-/- brain slices, but the intensity of these discharges was lower in PGC-1PV-/- slices, as evident from the reduced power in the gamma range and reduced firing rates in both PV interneurons and pyramidal cells during these discharges. Reflecting this reduced intensity in the pre-ictal discharges, the PGC-1PV-/- brain slices experienced many more discharges before transitioning into a seizure-like event. Consequently, there was a large increase in the latency to the first seizure-like event in brain slices lacking PGC-1 in PV interneurons. We conclude that knocking down PGC-1 limits the range of PV interneuron firing, and this slows the pathophysiological escalation during ictogenesis.