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- Title
PGC-1α Negatively Regulates Extrasynaptic NMDAR Activity and Excitotoxicity.
- Authors
Puddifoot, Clare; Martel, Marc-Andre; Soriano, Francesc X.; Camacho, Alberto; Vidal-Puig, Antonio; Wyllie, David J. A.; Hardingham1, Giles E.
- 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 (NMDAREX) activity. Here we show that PGC-1α controls NMDAREX activity in neurons and that its suppression contributes to mutant Huntingtin (mHtt)-induced increases in NMDAREX activity and vulnerability to excitotoxic insults. Wefound that knock-down of endogenous PGC-1α increasedNMDAREX activity and vulnerability to excitotoxic insults in rat cortical neurons. In contrast, exogenous expression of PGC-1α resulted in a neuroprotective reduction of NMDAREX currents without affecting synaptic NMDAR activity. Since HD models are associated with mHtt-mediated suppression of PGC-1α expression, as well as increased NMDAREX activity, we investigated whether these two events were linked. Expression of mHtt (148Q) resulted in a selective increase in NMDAREX 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 onNMDAREX 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 NMDAREX 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 NMDAREX activity in disorders where PGC-1α is underexpressed.
- Subjects
PGC-1 protein; GENETIC regulation; METHYL aspartate receptors; DISEASE progression; ENZYME activation; NEURONS; CELL death
- Publication
Journal of Neuroscience, 2012, Vol 32, Issue 20, p6995
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.6407-11.2012