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Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1618-E1626. doi: 10.1073/pnas.1716871115. Epub 2018 Jan 30.

Restoring GABAergic inhibition rescues memory deficits in a Huntington's disease mouse model.

Author information

1
Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.
2
Department of Psychology, University of Toronto, Toronto, ON M5S 3G3, Canada.
3
Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada; m.woodin@utoronto.ca.

Abstract

Huntington's disease (HD) is classically characterized as a movement disorder, however cognitive impairments precede the motor symptoms by ∼15 y. Based on proteomic and bioinformatic data linking the Huntingtin protein (Htt) and KCC2, which is required for hyperpolarizing GABAergic inhibition, and the important role of inhibition in learning and memory, we hypothesized that aberrant KCC2 function contributes to the hippocampal-associated learning and memory deficits in HD. We discovered that Htt and KCC2 interact in the hippocampi of wild-type and R6/2-HD mice, with a decrease in KCC2 expression in the hippocampus of R6/2 and YAC128 mice. The reduced expression of the Cl--extruding cotransporter KCC2 is accompanied by an increase in the Cl--importing cotransporter NKCC1, which together result in excitatory GABA in the hippocampi of HD mice. NKCC1 inhibition by the FDA-approved NKCC1 inhibitor bumetanide abolished the excitatory action of GABA and rescued the performance of R6/2 mice on hippocampal-associated behavioral tests.

KEYWORDS:

GABA; Huntington’s disease; chloride; learning; synaptic inhibition

PMID:
29382760
PMCID:
PMC5816181
DOI:
10.1073/pnas.1716871115
[Indexed for MEDLINE]
Free PMC Article

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