title: Enhanced GABAergic Inputs Contribute to Functional Alterations of Cholinergic Interneurons in the R6/2 Mouse Model of Huntington's Disease.
abstract: In Huntington's disease (HD), a hereditary neurodegenerative disorder, striatal medium-sized spiny neurons undergo degenerative changes. In contrast, large cholinergic interneurons (LCIs) are relatively spared. However, their ability to release acetylcholine (ACh) is impaired. The present experiments examined morphological and electrophysiological properties of LCIs in the R6/2 mouse model of HD. R6/2 mice show a severe, rapidly progressing phenotype. Immunocytochemical analysis of choline acetyltransferase-positive striatal neurons showed that, although the total number of cells was not changed, somatic areas were significantly smaller in symptomatic R6/2 mice compared to wildtype (WT) littermates, For electrophysiology, brain slices were obtained from presymptomatic (3-4 weeks) and symptomatic (>8 weeks) R6/2 mice and their WT littermates. Striatal LCIs were identified by somatic size and spontaneous action potential firing in the cell-attached mode. Passive and active membrane properties of LCIs were similar in presymptomatic R6/2 and WT mice. In contrast, LCIs from symptomatic R6/2 animals displayed smaller membrane capacitance and higher input resistance, consistent with reduced somatic size. In addition, more LCIs from symptomatic mice displayed irregular firing patterns and bursts of action potentials. They also displayed a higher frequency of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) and larger amplitude of electrically evoked IPSCs. Selective optogenetic stimulation of somatostatin- but not parvalbumin-containing interneurons also evoked larger amplitude IPSCs in LCIs from R6/2 mice. In contrast, glutamatergic spontaneous or evoked postsynaptic currents were not affected. Morphological and electrophysiological alterations, in conjunction with the presence of mutant huntingtin in LCIs, could explain impaired ACh release in HD mouse models.
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA 90095.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Holley
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA 90095.
authors.forename: Prasad R
authors.initials: PR
authors.lastname: Joshi
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA 90095.
authors.forename: Anna
authors.initials: A
authors.lastname: Parievsky
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA 90095.
authors.forename: Laurie
authors.initials: L
authors.lastname: Galvan
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA 90095.
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA 90095.
authors.forename: Yvette E
authors.initials: YE
authors.lastname: Fisher
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA 90095.
authors.forename: My N
authors.initials: MN
authors.lastname: Huynh
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA 90095.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cepeda
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA 90095.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Levine
keywords: GABA; Huntington’s disease; R6/2 mouse model; cholinergic interneurons; optogenetics; striatum