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.
journal_name
Proc Natl Acad Sci U S Aauthors
Dargaei Z,Bang JY,Mahadevan V,Khademullah CS,Bedard S,Parfitt GM,Kim JC,Woodin MAdoi
10.1073/pnas.1716871115subject
Has Abstractpub_date
2018-02-13 00:00:00pages
E1618-E1626issue
7eissn
0027-8424issn
1091-6490pii
1716871115journal_volume
115pub_type
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