{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:58:53Z","timestamp":1779929933940,"version":"3.53.1"},"reference-count":26,"publisher":"Society for Neuroscience","issue":"20","license":[{"start":{"date-parts":[[2012,11,16]],"date-time":"2012-11-16T00:00:00Z","timestamp":1353024000000},"content-version":"vor","delay-in-days":184,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2012,5,16]]},"abstract":"<jats:p>Underexpression of the transcriptional coactivator PGC-1\u03b1 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<jats:sup>EX<\/jats:sup>) activity. Here we show that PGC-1\u03b1 controls NMDAR<jats:sup>EX<\/jats:sup>activity in neurons and that its suppression contributes to mutant Huntingtin (mHtt)-induced increases in NMDAR<jats:sup>EX<\/jats:sup>activity and vulnerability to excitotoxic insults.<\/jats:p><jats:p>We found that knock-down of endogenous PGC-1\u03b1 increased NMDAR<jats:sup>EX<\/jats:sup>activity and vulnerability to excitotoxic insults in rat cortical neurons. In contrast, exogenous expression of PGC-1\u03b1 resulted in a neuroprotective reduction of NMDAR<jats:sup>EX<\/jats:sup>currents without affecting synaptic NMDAR activity. Since HD models are associated with mHtt-mediated suppression of PGC-1\u03b1 expression, as well as increased NMDAR<jats:sup>EX<\/jats:sup>activity, we investigated whether these two events were linked. Expression of mHtt (148Q) resulted in a selective increase in NMDAR<jats:sup>EX<\/jats:sup>activity, compared with wild-type Htt (18Q), and increased vulnerability to NMDA excitotoxicity. Importantly, we observed that the effects of mHtt and PGC-1\u03b1 knockdown on NMDAR<jats:sup>EX<\/jats:sup>activity and vulnerability to excitotoxicity were nonadditive and occluded each other, consistent with a common mechanism. Moreover, exogenous expression of PGC-1\u03b1 reversed mtHtt-mediated increases in NMDAR<jats:sup>EX<\/jats:sup>activity and protected neurons against excitotoxic cell death. The link between mHtt, PGC-1\u03b1, and NMDAR activity was also confirmed in rat striatal neurons. Thus, targeting levels of PGC-1\u03b1 expression may help reduce aberrant NMDAR<jats:sup>EX<\/jats:sup>activity in disorders where PGC-1\u03b1 is underexpressed.<\/jats:p>","DOI":"10.1523\/jneurosci.6407-11.2012","type":"journal-article","created":{"date-parts":[[2012,5,16]],"date-time":"2012-05-16T17:41:33Z","timestamp":1337190093000},"page":"6995-7000","source":"Crossref","is-referenced-by-count":56,"title":["PGC-1\u03b1 Negatively Regulates Extrasynaptic NMDAR Activity and Excitotoxicity"],"prefix":"10.1523","volume":"32","author":[{"given":"Clare","family":"Puddifoot","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc-Andre","family":"Martel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesc X.","family":"Soriano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Camacho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Vidal-Puig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J. A.","family":"Wyllie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giles E.","family":"Hardingham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2012,5,16]]},"reference":[{"key":"2023041303562622000_32.20.6995.1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4101-05.2006"},{"key":"2023041303562622000_32.20.6995.2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3021-10.2010"},{"key":"2023041303562622000_32.20.6995.3","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq229"},{"key":"2023041303562622000_32.20.6995.4","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1002\/jnr.22225","article-title":"Protective effects of peroxisome proliferator-activated receptors gamma coactivator-1alpha against neuronal cell death in the hippocampal CA1 subfield after transient global ischemia","volume":"88","author":"Chen","year":"2010","journal-title":"J Neurosci Res"},{"key":"2023041303562622000_32.20.6995.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.09.015"},{"key":"2023041303562622000_32.20.6995.6","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.52.3.642"},{"key":"2023041303562622000_32.20.6995.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2006.11.003"},{"key":"2023041303562622000_32.20.6995.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2009.03.006"},{"key":"2023041303562622000_32.20.6995.9","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2911"},{"key":"2023041303562622000_32.20.6995.10","doi-asserted-by":"publisher","DOI":"10.1038\/nn835"},{"key":"2023041303562622000_32.20.6995.11","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6017-08.2009"},{"key":"2023041303562622000_32.20.6995.12","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-009-9196-5"},{"key":"2023041303562622000_32.20.6995.13","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201000084"},{"key":"2023041303562622000_32.20.6995.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.01.008"},{"key":"2023041303562622000_32.20.6995.15","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-011-0850-z"},{"key":"2023041303562622000_32.20.6995.16","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2056"},{"key":"2023041303562622000_32.20.6995.17","doi-asserted-by":"publisher","DOI":"10.1038\/nn2071"},{"key":"2023041303562622000_32.20.6995.18","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2008.588"},{"key":"2023041303562622000_32.20.6995.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.010"},{"key":"2023041303562622000_32.20.6995.20","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2010.3568"},{"key":"2023041303562622000_32.20.6995.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.09.024"},{"key":"2023041303562622000_32.20.6995.22","doi-asserted-by":"publisher","DOI":"10.1126\/science.1172871"},{"key":"2023041303562622000_32.20.6995.23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.018911"},{"key":"2023041303562622000_32.20.6995.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2006.10.004"},{"key":"2023041303562622000_32.20.6995.25","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2488-10.2010"},{"key":"2023041303562622000_32.20.6995.26","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-6-51"}],"container-title":["The Journal of Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1523\/JNEUROSCI.6407-11.2012","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T16:38:27Z","timestamp":1713976707000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jneurosci.org\/lookup\/doi\/10.1523\/JNEUROSCI.6407-11.2012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,5,16]]},"references-count":26,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2012,5,16]]},"published-print":{"date-parts":[[2012,5,16]]}},"alternative-id":["10.1523\/JNEUROSCI.6407-11.2012"],"URL":"https:\/\/doi.org\/10.1523\/jneurosci.6407-11.2012","relation":{},"ISSN":["0270-6474","1529-2401"],"issn-type":[{"value":"0270-6474","type":"print"},{"value":"1529-2401","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,5,16]]}}}