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Holley SM, Joshi PR, Parievsky A, et al. Enhanced GABAergic Inputs Contribute to Functional Alterations of Cholinergic Interneurons in the R6/2 Mouse Model of Huntington's Disease. eNeuro. 2015;2(1)doi: 10.1523/ENEURO.0008-14.2015.
Holley, S. M., Joshi, P. R., Parievsky, A., Galvan, L., Chen, J. Y., Fisher, Y. E., Huynh, M. N., Cepeda, C., & Levine, M. S. (2015). Enhanced GABAergic Inputs Contribute to Functional Alterations of Cholinergic Interneurons in the R6/2 Mouse Model of Huntington's Disease. eNeuro, 2(1), . https://doi.org/10.1523/ENEURO.0008-14.2015
Holley, Sandra M, et al. "Enhanced GABAergic Inputs Contribute to Functional Alterations of Cholinergic Interneurons in the R6/2 Mouse Model of Huntington's Disease." eNeuro vol. 2,1 (2015). doi: https://doi.org/10.1523/ENEURO.0008-14.2015
Holley SM, Joshi PR, Parievsky A, Galvan L, Chen JY, Fisher YE, Huynh MN, Cepeda C, Levine MS. Enhanced GABAergic Inputs Contribute to Functional Alterations of Cholinergic Interneurons in the R6/2 Mouse Model of Huntington's Disease. eNeuro. 2015 Jan-Feb;2(1). doi: 10.1523/ENEURO.0008-14.2015. PMID: 26203463; PMCID: PMC4507822.
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eNeuro. 2015 Jan-Feb;2(1). doi: 10.1523/ENEURO.0008-14.2015.

Enhanced GABAergic Inputs Contribute to Functional Alterations of Cholinergic Interneurons in the R6/2 Mouse Model of Huntington's Disease.

eNeuro

Sandra M Holley, Prasad R Joshi, Anna Parievsky, Laurie Galvan, Jane Y Chen, Yvette E Fisher, My N Huynh, Carlos Cepeda, Michael S Levine

Affiliations

  1. Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA 90095.

PMID: 26203463 PMCID: PMC4507822 DOI: 10.1523/ENEURO.0008-14.2015

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.

Keywords: GABA; Huntington’s disease; R6/2 mouse model; cholinergic interneurons; optogenetics; striatum

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