{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T23:01:56Z","timestamp":1793833316169,"version":"4.6.1"},"reference-count":63,"publisher":"Society for Neuroscience","issue":"50","license":[{"start":{"date-parts":[[2008,6,12]],"date-time":"2008-06-12T00:00:00Z","timestamp":1213228800000},"content-version":"vor","delay-in-days":183,"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":[[2007,12,12]]},"abstract":"<jats:p>Expansion of a CAG repeat in the Huntington's disease (HD) gene results in progressive neuronal loss, particularly of striatal medium-sized spiny neurons (MSNs). Studies in human HD autopsy brain tissue, as well as cellular and animal models of HD, suggest that increased activity of NMDA-type glutamate receptors and altered mitochondrial function contribute to selective neuronal degeneration. In this regard, the YAC128 mouse model, expressing full-length human huntingtin with 128 glutamine repeats, has been the focus of much interest. Although NMDA-induced apoptosis is enhanced in YAC128 MSNs, here we report that the initial steps in the death signaling pathway, including NMDA receptor (NMDAR) current and cytosolic Ca<jats:sup>2+<\/jats:sup>loading, are similar to those observed in wild-type MSNs. In contrast, we found that the NMDAR-mediated Ca<jats:sup>2+<\/jats:sup>load triggered a strikingly enhanced loss of mitochondrial membrane potential in YAC128 MSNs, suggesting that NMDAR signaling via the mitochondrial apoptotic pathway is altered. This effect was accompanied by impaired cytosolic Ca<jats:sup>2+<\/jats:sup>clearance after removal of NMDA, a difference that was not apparent after high potassium-evoked depolarization-mediated Ca<jats:sup>2+<\/jats:sup>entry. Inhibition of the mitochondrial permeability transition (mPT) reduced peak cytosolic Ca<jats:sup>2+<\/jats:sup>and mitochondrial depolarization evoked by NMDA in YAC128 MSNs but not wild-type MSNs. Hence, in contrast to YAC models with moderate CAG expansions, the enhanced NMDA-induced apoptosis in YAC128 MSNs is predominantly determined by augmented mitochondrial sensitivity to Ca<jats:sup>2+<\/jats:sup>-induced activation of the mPT. These results suggest that the CAG repeat length influences the mechanism by which mHtt enhances NMDAR-mediated excitotoxicity.<\/jats:p>","DOI":"10.1523\/jneurosci.3455-07.2007","type":"journal-article","created":{"date-parts":[[2007,12,12]],"date-time":"2007-12-12T17:28:38Z","timestamp":1197480518000},"page":"13614-13623","source":"Crossref","is-referenced-by-count":105,"title":["Mitochondrial Sensitivity and Altered Calcium Handling Underlie Enhanced NMDA-Induced Apoptosis in YAC128 Model of Huntington's Disease"],"prefix":"10.1523","volume":"27","author":[{"given":"Herman B.","family":"Fernandes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth G.","family":"Baimbridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Church","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Hayden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn A.","family":"Raymond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2007,12,12]]},"reference":[{"key":"2023041303290532000_27.50.13614.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(97)00162-0"},{"key":"2023041303290532000_27.50.13614.2","doi-asserted-by":"crossref","unstructured":"Alano CC Beutner G Dirksen RT Gross RA Sheu SS Mitochondrial permeability transition and calcium dynamics in striatal neurons upon intense NMDA receptor activation. J Neurochem 80:531\u2013538.","DOI":"10.1046\/j.0022-3042.2001.00738.x"},{"key":"2023041303290532000_27.50.13614.3","doi-asserted-by":"publisher","DOI":"10.1038\/nn1000"},{"key":"2023041303290532000_27.50.13614.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.11.049"},{"key":"2023041303290532000_27.50.13614.5","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1962.04210040027003"},{"key":"2023041303290532000_27.50.13614.6","doi-asserted-by":"publisher","DOI":"10.1086\/301612"},{"key":"2023041303290532000_27.50.13614.7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2001.0793h.x"},{"key":"2023041303290532000_27.50.13614.8","doi-asserted-by":"crossref","first-page":"4858","DOI":"10.1523\/JNEUROSCI.23-12-04858.2003","article-title":"Increased susceptibility of striatal mitochondria to calcium-induced permeability transition","volume":"23","author":"Brustovetsky","year":"2003","journal-title":"J Neurosci"},{"key":"2023041303290532000_27.50.13614.9","doi-asserted-by":"crossref","first-page":"10277","DOI":"10.1523\/JNEUROSCI.18-24-10277.1998","article-title":"Mitochondrial control of acute glutamate excitotoxicity in cultured cerebellar granule cells","volume":"18","author":"Castilho","year":"1998","journal-title":"J Neurosci"},{"key":"2023041303290532000_27.50.13614.10","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.1244"},{"key":"2023041303290532000_27.50.13614.11","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1523\/JNEUROSCI.23-03-00961.2003","article-title":"Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington's disease","volume":"23","author":"Cepeda","year":"2003","journal-title":"J Neurosci"},{"key":"2023041303290532000_27.50.13614.12","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(00)01609-X"},{"key":"2023041303290532000_27.50.13614.13","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1999.0721890.x"},{"key":"2023041303290532000_27.50.13614.14","doi-asserted-by":"publisher","DOI":"10.1124\/mol.59.2.212"},{"key":"2023041303290532000_27.50.13614.15","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddh162"},{"key":"2023041303290532000_27.50.13614.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2005.10.011"},{"key":"2023041303290532000_27.50.13614.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2006.11.003"},{"key":"2023041303290532000_27.50.13614.18","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4356-06.2007"},{"key":"2023041303290532000_27.50.13614.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2005.08.007"},{"key":"2023041303290532000_27.50.13614.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.04.026"},{"key":"2023041303290532000_27.50.13614.21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.15.8727"},{"key":"2023041303290532000_27.50.13614.22","doi-asserted-by":"publisher","DOI":"10.1046\/j.0953-816x.2001.01767.x"},{"key":"2023041303290532000_27.50.13614.23","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80737-0"},{"key":"2023041303290532000_27.50.13614.24","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80764-3"},{"key":"2023041303290532000_27.50.13614.25","doi-asserted-by":"crossref","first-page":"6669","DOI":"10.1523\/JNEUROSCI.17-17-06669.1997","article-title":"Ionized intracellular calcium concentration predicts excitotoxic neuronal death: observations with low-affinity fluorescent calcium indicators","volume":"17","author":"Hyrc","year":"1997","journal-title":"J Neurosci"},{"key":"2023041303290532000_27.50.13614.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.04.031"},{"key":"2023041303290532000_27.50.13614.27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.221451398"},{"key":"2023041303290532000_27.50.13614.28","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.2000.7576"},{"key":"2023041303290532000_27.50.13614.29","doi-asserted-by":"crossref","first-page":"9112","DOI":"10.1523\/JNEUROSCI.21-23-09112.2001","article-title":"Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington's disease","volume":"21","author":"Laforet","year":"2001","journal-title":"J Neurosci"},{"key":"2023041303290532000_27.50.13614.30","doi-asserted-by":"publisher","DOI":"10.1086\/318207"},{"key":"2023041303290532000_27.50.13614.31","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00308.2004"},{"key":"2023041303290532000_27.50.13614.32","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3990-05.2006"},{"key":"2023041303290532000_27.50.13614.33","doi-asserted-by":"publisher","DOI":"10.1126\/science.1096615"},{"key":"2023041303290532000_27.50.13614.34","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.9.1259"},{"key":"2023041303290532000_27.50.13614.35","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1697-04.2004"},{"key":"2023041303290532000_27.50.13614.36","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1113\/jphysiol.1989.sp017724","article-title":"Modulation of excitatory amino acid receptors by group IIB metal cations in cultured mouse hippocampal neurones","volume":"415","author":"Mayer","year":"1989","journal-title":"J Physiol (Lond)"},{"key":"2023041303290532000_27.50.13614.37","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3004-06.2006"},{"key":"2023041303290532000_27.50.13614.38","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-005-3454-9"},{"key":"2023041303290532000_27.50.13614.39","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-9861(02)00585-4"},{"key":"2023041303290532000_27.50.13614.40","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/nn884","article-title":"Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines","volume":"5","author":"Panov","year":"2002","journal-title":"Nat Neurosci"},{"key":"2023041303290532000_27.50.13614.41","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(96)00089-9"},{"key":"2023041303290532000_27.50.13614.42","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(02)00872-3"},{"key":"2023041303290532000_27.50.13614.43","doi-asserted-by":"publisher","DOI":"10.1038\/13518"},{"key":"2023041303290532000_27.50.13614.44","doi-asserted-by":"crossref","first-page":"6125","DOI":"10.1523\/JNEUROSCI.16-19-06125.1996","article-title":"Mitochondrial dysfunction is a primary event in glutamate neurotoxicity","volume":"16","author":"Schinder","year":"1996","journal-title":"J Neurosci"},{"key":"2023041303290532000_27.50.13614.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2005.08.001"},{"key":"2023041303290532000_27.50.13614.46","doi-asserted-by":"crossref","first-page":"4548","DOI":"10.1523\/JNEUROSCI.14-07-04548.1994","article-title":"GABA synapses formed in vitro by local axon collaterals of nucleus accumbens neurons","volume":"14","author":"Shi","year":"1994","journal-title":"J Neurosci"},{"key":"2023041303290532000_27.50.13614.47","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg169"},{"key":"2023041303290532000_27.50.13614.48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0503634102"},{"key":"2023041303290532000_27.50.13614.49","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(98)00441-2"},{"key":"2023041303290532000_27.50.13614.50","doi-asserted-by":"publisher","DOI":"10.1038\/1577"},{"key":"2023041303290532000_27.50.13614.51","doi-asserted-by":"publisher","DOI":"10.1038\/ng1193-259"},{"key":"2023041303290532000_27.50.13614.52","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00366-0"},{"key":"2023041303290532000_27.50.13614.53","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0409402102"},{"key":"2023041303290532000_27.50.13614.54","doi-asserted-by":"publisher","DOI":"10.1007\/s004240000390"},{"key":"2023041303290532000_27.50.13614.55","doi-asserted-by":"publisher","DOI":"10.1007\/BF00401235"},{"key":"2023041303290532000_27.50.13614.56","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0590-05.2005"},{"key":"2023041303290532000_27.50.13614.57","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-198511000-00003"},{"key":"2023041303290532000_27.50.13614.58","doi-asserted-by":"crossref","first-page":"7862","DOI":"10.1523\/JNEUROSCI.22-18-07862.2002","article-title":"Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease","volume":"22","author":"Wellington","year":"2002","journal-title":"J Neurosci"},{"key":"2023041303290532000_27.50.13614.59","first-page":"851","article-title":"Ifenprodil discriminates subtypes of the N-methyl-d-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors","volume":"44","author":"Williams","year":"1993","journal-title":"Mol Pharmacol"},{"key":"2023041303290532000_27.50.13614.60","doi-asserted-by":"crossref","first-page":"10761","DOI":"10.1523\/JNEUROSCI.22-24-10761.2002","article-title":"Changes in mitochondrial status associated with altered Ca2+ homeostasis in aged cerebellar granule neurons in brain slices","volume":"22","author":"Xiong","year":"2002","journal-title":"J Neurosci"},{"key":"2023041303290532000_27.50.13614.61","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(02)00615-3"},{"key":"2023041303290532000_27.50.13614.62","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2003.11.014"},{"key":"2023041303290532000_27.50.13614.63","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059581"}],"container-title":["The Journal of Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1523\/JNEUROSCI.3455-07.2007","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T18:26:25Z","timestamp":1681410385000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jneurosci.org\/lookup\/doi\/10.1523\/JNEUROSCI.3455-07.2007"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,12,12]]},"references-count":63,"journal-issue":{"issue":"50","published-online":{"date-parts":[[2007,12,12]]},"published-print":{"date-parts":[[2007,12,12]]}},"alternative-id":["10.1523\/JNEUROSCI.3455-07.2007"],"URL":"https:\/\/doi.org\/10.1523\/jneurosci.3455-07.2007","relation":{},"ISSN":["0270-6474","1529-2401"],"issn-type":[{"value":"0270-6474","type":"print"},{"value":"1529-2401","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,12,12]]}}}