title: Early dysfunction and progressive degeneration of the subthalamic nucleus in mouse models of Huntington's disease.
abstract: The subthalamic nucleus (STN) is an element of cortico-basal ganglia-thalamo-cortical circuitry critical for action suppression. In Huntington's disease (HD) action suppression is impaired, resembling the effects of STN lesioning or inactivation. To explore this potential linkage, the STN was studied in BAC transgenic and Q175 knock-in mouse models of HD. At <2 and 6 months of age autonomous STN activity was impaired due to activation of KATPchannels. STN neurons exhibited prolonged NMDA receptor-mediated synaptic currents, caused by a deficit in glutamate uptake, and elevated mitochondrial oxidant stress, which was ameliorated by NMDA receptor antagonism. STN activity was rescued by NMDA receptor antagonism or the break down of hydrogen peroxide. At 12 months of age approximately 30% of STN neurons had been lost, as in HD. Together, these data argue that dysfunction within the STN is an early feature of HD that may contribute to its expression and course.
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, United States.
authors.forename: Jeremy F
authors.initials: JF
authors.lastname: Atherton
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, United States.
authors.forename: Eileen L
authors.initials: EL
authors.lastname: McIver
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, United States.
authors.forename: Matthew Rm
authors.initials: MR
authors.lastname: Mullen
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Wokosin
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, United States.
authors.forename: D James
authors.initials: DJ
authors.lastname: Surmeier
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, United States.
authors.forename: Mark D
authors.identifier: 0000-0001-9759-0163
authors.initials: MD
authors.lastname: Bevan
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D006816:Huntington Disease / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology; D009474:Neurons / Q000502:physiology; D018384:Oxidative Stress; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D020531:Subthalamic Nucleus / Q000473:pathology* / Q000503:physiopathology*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate
keywords: KATP channels; NMDA receptors; astrocytes; basal ganglia; glutamate; mitochondria; mouse; neuroscience