Abstract
The transcriptional coactivator, PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α), 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-1α levels. In cortical networks, PGC-1α is required for the induction of parvalbumin (PV) expression in interneurons, and PGC-1α deficiency affects synchronous GABAergic release. It is unknown, however, how this affects cortical excitability. We show here that knocking down PGC-1α specifically in the PV-expressing cells (PGC-1αPV-/-) blocks the activity-dependent regulation of the synaptic proteins, SYT2 and CPLX1. More surprisingly, this cell class-specific knockout of PGC-1α 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-1αPV-/- brain slices, but the intensity of these discharges was lower in PGC-1αPV-/- slices, as evident from the reduced power in the γ 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-1αPV-/- 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-1α in PV interneurons. We conclude that knocking down PGC-1α 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-1α, 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-1α knockdown may promote schizophrenia while reducing epileptic tendencies.
Highlights
Studies in nonneuronal tissue have identified the transcriptional coactivator, PGC-1a, as a key regulator of expression of nuclear-encoded mitochondrial genes [1,2,3,4]
The lack of change in gene expression in PGC-1aPVÀ/À brain slices was not due to a lack of epileptiform activity during the hour exposure to 0 Mg2 þ artificial cerebrospinal fluid (aCSF); both sets of brain slices showed the distinctive pattern of evolving pathological discharges (Fig. 2A), starting with transient discharges lasting a few hundred milliseconds, and at longer latency, the appearance of sustained rhythmic discharges lasting tens of seconds, which we term seizure-like events (SLEs)
We found that PV firing rates were significantly lower in the PGC-1aPVÀ/À brain slices compared with wildtype brain slices before the first SLE (Fig. 6Ai), this difference was not maintained in later interictal events (Fig. 6Aii)
Summary
Studies in nonneuronal tissue have identified the transcriptional coactivator, PGC-1a (peroxisome proliferator-activated receptor c coactivator 1a), as a key regulator of expression of nuclear-encoded mitochondrial genes [1,2,3,4]. LOSS OF CORTICAL PGC-1a SLOWS DOWN ICTOGENESIS dose-dependent manner, without affecting the expression of other interneuronal markers, whereas overexpression of PGC1a in cultured neurons strongly induces PV expression [10]. PV interneurons are among the most active of any cortical neuronal class; they characteristically fire on every cycle of c oscillations [13,14,15] and show extremely high firing rates ahead of an ictal wave front [16, 17] These various considerations, their apparent high metabolism and the powerful effect that PV interneurons exert upon cortical networks, have led to the suggestion that PV interneurons may be susceptible to metabolic stress, which in turn could give rise to neuropathology [18, 19]. Germline knockdown of PGC-1a is associated with hyperactive behavior [27], this is believed to be a behavioral adaptation to a reduction in thermogenesis capacity in brown fat and muscle, because the hyperactive phenotype was not replicated in mice with central nervous system deletion of PGC-1a [28]
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