title: Forebrain striatal-specific expression of mutant huntingtin protein in vivo induces cell-autonomous age-dependent alterations in sensitivity to excitotoxicity and mitochondrial function.
abstract: HD (Huntington's disease) is characterized by dysfunction and death of striatal MSNs (medium-sized spiny neurons). Excitotoxicity, transcriptional dysregulation and mitochondrial abnormalities are among the mechanisms that are proposed to play roles in HD pathogenesis. To determine the extent of cell-autonomous effects of mhtt (mutant huntingtin) protein on vulnerability to excitotoxic insult in MSNs in vivo, we measured the number of degenerating neurons in response to intrastriatal injection of QA (quinolinic acid) in presymptomatic and symptomatic transgenic (D9-N171-98Q, also known as DE5) mice that express mhtt in MSNs but not in cortex. After QA, the number of degenerating neurons in presymptomatic DE5 mice was not significantly different from the number in WT (wild-type) controls, suggesting the early, increased vulnerability to excitotoxicity demonstrated in other HD mouse models has a largely non-cell-autonomous component. Conversely, symptomatic DE5 mice showed significantly fewer degenerating neurons relative to WT, implying the resistance to excitotoxicity observed at later ages has a primarily cell-autonomous origin. Interestingly, mitochondrial complex II respiration was enhanced in striatum of symptomatic mice, whereas it was reduced in presymptomatic mice, both relative to their age-matched controls. Consistent with the QA data, MSNs from symptomatic mice showed decreased NMDA (N-methyl-d-aspartate) currents compared with age-matched controls, suggesting that in addition to aging, cell-autonomous mechanisms mitigate susceptibility to excitotoxicity in the symptomatic stage. Also, symptomatic DE5 mice did not display some of the electrophysiological alterations present in other HD models, suggesting that blocking the expression of mhtt in cortical neurons may restore corticostriatal function in HD.
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, NY, U.S.A.
authors.forename: Soong Ho
authors.initials: SH
authors.lastname: Kim
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Thomas
authors.forename: Véronique M
authors.initials: VM
authors.lastname: André
authors.forename: Damian M
authors.initials: DM
authors.lastname: Cummings
authors.forename: Carlos
authors.initials: C
authors.lastname: Cepeda
authors.forename: Michael S
authors.initials: MS
authors.lastname: Levine
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Ehrlich
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D004195:Disease Models, Animal; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D042963:Electron Transport Complex II / Q000502:physiology; D004594:Electrophysiology; D000071058:Huntingtin Protein; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D016202:N-Methylaspartate / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016548:Prosencephalon / Q000033:anatomy & histology / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D017378:Quinolinic Acid / Q000494:pharmacology
chemical_list: D045222:Electron Transport Chain Complex Proteins; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016202:N-Methylaspartate; D042963:Electron Transport Complex II; D017378:Quinolinic Acid