Enhanced Na+‐K+‐2Cl‐ cotransporter 1 underlies motor dysfunction in huntington's disease

Abstract Background Altered γ ‐aminobutyric acid signaling is believed to disrupt the excitation/inhibition balance in the striatum, which may account for the motor symptoms of Huntington's disease. Na‐K‐2Cl cotransporter‐1 is a key molecule that controls γ ‐aminobutyric acid ‐ergic signaling. However, the role of Na‐K‐2Cl cotransporter‐1 and efficacy of γ ‐aminobutyric acid ‐ergic transmission remain unknown in Huntington's disease. Methods We determined the levels of Na‐K‐2Cl cotransporter‐1 in brain tissue from Huntington's disease mice and patients by real‐time quantitative polymerase chain reaction, western blot, and immunocytochemistry. Gramicidin‐perforated patch‐clamp recordings were used to measure the E γ ‐aminobutyric acid in striatal brain slices. To inhibit Na‐K‐2Cl cotransporter‐1 activity, R6/2 mice were treated with an intraperitoneal injection of bumetanide or adeno‐associated virus‐mediated delivery of Na‐K‐2Cl cotransporter‐1 short‐hairpin RNA into the striatum. Motor behavior assays were employed. Results Expression of Na‐K‐2Cl cotransporter‐1 was elevated in the striatum of R6/2 and Hdh 150Q/7Q mouse models. An increase in Na‐K‐2Cl cotransporter‐1 transcripts was also found in the caudate nucleus of Huntington's disease patients. Accordingly, a depolarizing shift of E γ ‐aminobutyric acid was detected in the striatum of R6/2 mice. Expression of the mutant huntingtin in astrocytes and neuroinflammation were necessary for enhanced expression of Na‐K‐2Cl cotransporter‐1 in HD mice. Notably, pharmacological or genetic inhibition of Na‐K‐2Cl cotransporter‐1 rescued the motor deficits of R6/2 mice. Conclusions Our findings demonstrate that aberrant γ ‐aminobutyric acid ‐ergic signaling and enhanced Na‐K‐2Cl cotransporter‐1 contribute to the pathogenesis of Huntington's disease and identify a new therapeutic target for the potential rescue of motor dysfunction in patients with Huntington's disease. © 2019 International Parkinson and Movement Disorder Society