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Title: PGC-1α negatively regulates extrasynaptic NMDAR activity and excitotoxicity
Author: Puddifoot, Clare
Martel, Marc-André
Soriano Zaragoza, Francesc X. (Francesc Xavier)
Camacho, Alberto
Vidal Puig, Antonio
Wyllie, David J. A.
Hardingham, Gilles E.
Keywords: Malalties neurodegeneratives
Corea de Huntington
Regulació genètica
Neurodegenerative diseases
Huntington's chorea
Genetic regulation
Issue Date: 16-May-2012
Publisher: The Society for Neuroscience
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 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 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 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 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.
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It is part of: Journal of Neuroscience, 2012, vol. 32, num. 20, p. 6995-7000
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ISSN: 0270-6474
Appears in Collections:Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)

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