Authors

Holley, S. M. Joshi, P. R. Parievsky, A. Galvan, L. Chen, J. Y. Fisher, Y. E. Huynh, M. N. Cepeda, C. Levine, M. S.

Affiliations

Intellectual and Developmental Disabilities Research Centre, Semel Institute for Neuroscience and Human Behaviour, University of California at Los Angeles, Los Angeles, California 90095.

Topic

Optogenetics

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. Significance Statement: Although large cholinergic interneurons (LCIs) in striatum are spared in Huntington's disease (HD), deficits in cholinergic function have been described. Here we demonstrate in a mouse model of HD that the firing patterns of LCIs are disrupted and this is due to aberrant GABAergic neurotransmission. This explains cholinergic deficits in HD.

Extract

… “activated with a single light pulse (470 nm, 0.5 ms, 10 mW, CoolLED) delivered through the epifluores- cence illumination pathway using Chroma Technologies filter cubes. eIPSCs”…

Product Associated Features

pE-100: A range of compact, simple-to-use, single wavelength illumination systems for screening fluorescence.

Product Type

pE-100

Journal

eNeuro

Year of Publication

2015

Country of Publication

USA