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Research ArticleNew Research, Disorders of the Nervous System

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

Sandra M. Holley, Prasad R. Joshi, Anna Parievsky, Laurie Galvan, Jane Y. Chen, Yvette E. Fisher, My N. Huynh, Carlos Cepeda and Michael S. Levine
eNeuro 24 February 2015, 2 (1) ENEURO.0008-14.2015; https://doi.org/10.1523/ENEURO.0008-14.2015
Sandra M. Holley
Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, California 90095
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Prasad R. Joshi
Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, California 90095
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Anna Parievsky
Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, California 90095
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Laurie Galvan
Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, California 90095
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Jane Y. Chen
Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, California 90095
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Yvette E. Fisher
Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, California 90095
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My N. Huynh
Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, California 90095
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Carlos Cepeda
Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, California 90095
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Michael S. Levine
Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, California 90095
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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 wild-type (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 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.

  • cholinergic interneurons
  • GABA
  • Huntington’s disease
  • optogenetics
  • R6/2 mouse model
  • striatum

Footnotes

  • ↵1 The authors report no financial conflicts of interest.

  • ↵3 This work was supported by Cure HD Initiative, Inc. and USPHS Grant NS41574.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Enhanced GABAergic Inputs Contribute to Functional Alterations of Cholinergic Interneurons in the R6/2 Mouse Model of Huntington’s Disease
Sandra M. Holley, Prasad R. Joshi, Anna Parievsky, Laurie Galvan, Jane Y. Chen, Yvette E. Fisher, My N. Huynh, Carlos Cepeda, Michael S. Levine
eNeuro 24 February 2015, 2 (1) ENEURO.0008-14.2015; DOI: 10.1523/ENEURO.0008-14.2015

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Enhanced GABAergic Inputs Contribute to Functional Alterations of Cholinergic Interneurons in the R6/2 Mouse Model of Huntington’s Disease
Sandra M. Holley, Prasad R. Joshi, Anna Parievsky, Laurie Galvan, Jane Y. Chen, Yvette E. Fisher, My N. Huynh, Carlos Cepeda, Michael S. Levine
eNeuro 24 February 2015, 2 (1) ENEURO.0008-14.2015; DOI: 10.1523/ENEURO.0008-14.2015
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Keywords

  • cholinergic interneurons
  • GABA
  • Huntington’s disease
  • optogenetics
  • R6/2 mouse model
  • striatum

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