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

The transcriptional coactivator, PGC-1 alpha (peroxisome proliferator-activated receptor gamma coactivator 1 alpha), plays a key role in 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 alpha levels. In cortical networks, PGC-1 alpha is required for the induction of parvalbumin (PV) expression in interneurons, and PGC-1 alpha deficiency affects synchronous GABAergic release. It is unknown, however, how this affects cortical excitability. We show here that knocking down PGC-1 alpha specifically in the PV-expressing cells (PGC-1 alpha(PV-/-)) blocks the activity-dependent regulation of the synaptic proteins, SYT2 and CPLX1. More surprisingly, this cell class-specific knockout of PGC-1 alpha appears to have a novel antiepileptic effect, as assayed in brain slices bathed in 0 Mg2+ media. The rate of occurrence of preictal discharges developed approximately equivalently in wild-type and PGC-1 alpha(PV-/-) brain slices, but the intensity of these discharges was lower in PGC-1 alpha(PV-/-) slices, as evident from the reduced power in the y range and reduced firing rates in both PV interneurons and pyramidal cells during these discharges. Reflecting this reduced intensity in the preictal discharges, the PGC-1 alpha(PV-/-) 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 alpha in PV interneurons. We conclude that knocking down PGC-1 alpha limits the range of PV interneuron firing and this slows the pathophysiological escalation during ictogenesis. NEW & NOTEWORTHY Parvalbumin expressing interneurons are considered to play an important role in regulating cortical activity. We were surprised, therefore, to find that knocking down the transcriptional coactivator, PGC-1 alpha, specifically in this class of interneurons appears to slow ictogenesis. This anti-ictogenic effect is associated with reduced activity in preictal discharges, but with a far longer period of these discharges before the first seizure-like events finally start. Thus, PGC-1 alpha knockdown may promote schizophrenia while reducing epileptic tendencies.

Automated summary

The study demonstrates that knocking down the transcriptional coactivator PGC-1 alpha in PV-expressing cells in the cortical network produces an antiepileptic effect, reducing the activity of epileptic discharges and extending the period before the onset of seizure events.