title: Differential electrophysiological changes in striatal output neurons in Huntington's disease.
abstract: There is considerable evidence that alterations in striatal medium-sized spiny neurons (MSSNs) giving rise to the direct (D1 receptor-expressing) and indirect (D2 receptor-expressing) pathways differentially contribute to the phenotype of Huntington's disease (HD). To determine how each subpopulation of MSSN is functionally affected, we examined spontaneous excitatory postsynaptic currents (sEPSCs) and dopamine (DA) modulation in two HD mouse models, the YAC128 and the BACHD (a bacterial-artificial chromosome). These mice also expressed enhanced green fluorescent protein (EGFP) under the control of the promoter for either DA D1 or D2 receptors to identify neurons. In early symptomatic YAC128 and BACHD mice, glutamate transmission was increased in both D1 and D2 MSSNs, but in different ways. D1 cells displayed increased sEPSC frequencies and decreased paired-pulse ratios (PPRs) while D2 cells displayed larger evoked glutamate currents but no change in sEPSC frequencies or PPRs. D1 receptor modulation of sEPSCs was absent in D1-YAC128 cells at the early symptomatic stage but was restored by treating the slices with tetrabenazine. In contrast, in fully symptomatic YAC128 mice, glutamate transmission was decreased specifically in D1 cells, and D1 receptor modulation was normal in D1-YAC128 cells. Behaviorally, early symptomatic mice showed increased stereotypies that were decreased by tetrabenazine treatment. Together, these studies support differential imbalances in glutamate and DA transmission in direct and indirect pathway MSSNs. Stereotypic behavior at an early stage could be explained by increased glutamate activity and DA tone in direct pathway neurons, whereas hypokinesia at later stages could result from reduced input onto these neurons.
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, LA, CA 90095, USA. vandre@mednet.ucla.edu
authors.forename: Véronique M
authors.initials: VM
authors.lastname: André
authors.forename: Carlos
authors.initials: C
authors.lastname: Cepeda
authors.forename: Yvette E
authors.initials: YE
authors.lastname: Fisher
authors.forename: My
authors.initials: M
authors.lastname: Huynh
authors.forename: Nora
authors.initials: N
authors.lastname: Bardakjian
authors.forename: Sumedha
authors.initials: S
authors.lastname: Singh
authors.forename: X William
authors.initials: XW
authors.lastname: Yang
authors.forename: Michael S
authors.initials: MS
authors.lastname: Levine
mesh_terms: D000200:Action Potentials; D000367:Age Factors; D000818:Animals; D003342:Corpus Striatum / Q000503:physiopathology; D049229:Dendritic Spines / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials; D018698:Glutamic Acid / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006816:Huntington Disease / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity; D009474:Neurons / Q000502:physiology*; D011401:Promoter Regions, Genetic; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000235:genetics / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000502:physiology; D013239:Stereotyped Behavior; D009435:Synaptic Transmission; D013747:Tetrabenazine / Q000494:pharmacology
chemical_list: D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D004298:Dopamine; D013747:Tetrabenazine