PGC-1α: Negatively regulates extrasynaptic NMDAR activity and excitotoxicity

Abstract

Underexpression of the transcriptional coactivator PGC-1α is causally linked to certain neurodegenerative disorders, including Huntington's Disease (HD). HD pathoprogression is also associated with aberrant NMDAR EX activity, in particular an imbalance between synaptic versus extrasynaptic (NMDAR EX) activity. Here we show that PGC-1α controls NMDAR EX activity in neurons and that its suppression contributes to mutant Huntingtin (mHtt)-induced increases in NMDAR EX activity and vulnerability to excitotoxic insults. We found that knock-down of endogenous PGC-1α increased NMDAR EX activity and vulnerability to excitotoxic insults in rat cortical neurons. In contrast, exogenous expression of PGC-1α resulted in a neuroprotective reduction of NMDAR EX currents without affecting synaptic NMDAR EX activity. Since HD models are associated with mHtt-mediated suppression of PGC-1α expression, as well as increased NMDAR EX activity, we investigated whether these two events were linked. Expression of mHtt (148Q) resulted in a selective increase in NMDAR EX activity, compared with wild-type Htt (18Q), and increased vulnerability to NMDA EX excitotoxicity. Importantly, we observed that the effects of mHtt and PGC-1α knockdown on NMDAR EX activity and vulnerability to excitotoxicity were nonadditive and occluded each other, consistent with a common mechanism. Moreover, exogenous expression of PGC-1α reversed mtHtt-mediated increases in NMDAR EX activity and protected neurons against excitotoxic cell death. The link between mHtt, PGC-1α, and NMDAR EX activity was also confirmed in rat striatal neurons. Thus, targeting levels of PGC-1α expression may help reduce aberrant NMDAR EX activity in disorders where PGC-1α is underexpressed. © 2012 the authors.