title: 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 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.
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.
authors.forename: Clare
authors.initials: C
authors.lastname: Puddifoot
authors.forename: Marc-Andre
authors.initials: MA
authors.lastname: Martel
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Soriano
authors.forename: Alberto
authors.initials: A
authors.lastname: Camacho
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
authors.forename: David J A
authors.initials: DJ
authors.lastname: Wyllie
authors.forename: Giles E
authors.initials: GE
authors.lastname: Hardingham
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques / Q000379:methods; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology*; D016202:N-Methylaspartate / Q000633:toxicity*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors; D016202:N-Methylaspartate