Altered behavioral responses to gamma‐aminobutyric acid pharmacological agents in a mouse model of Huntington's disease

ABSTRACTBackground: Disruptions in gamma‐aminobutyric (GABA) acid signaling are believed to be involved in Huntington's disease pathogenesis, but the regulation of GABAergic signaling remains elusive. Here we evaluated GABAergic signaling by examining the function of GABAergic drugs in Huntington's disease and the expression of GABAergic molecules using mouse models and human brain tissues from Huntington's disease.Methods: We treated wild‐type and R6/2 mice (a transgenic Huntington's disease mouse model) acutely with vehicle, diazepam, or gaboxadol (drugs that selectively target synaptic or extrasynaptic GABAA receptors) and monitored their locomotor activity. The expression levels of GABAA receptors and a major neuron‐specific chloride extruder (potassium‐chloride cotransporter‐2) were analyzed by real‐time quantitative polymerase chain reaction, Western blot, and immunocytochemistry.Results: The R6/2 mice were less sensitive to the sedative effects of both drugs, suggesting reduced function of GABAA receptors. Consistently, the expression levels of α1/α2 and δ subunits were lower in the cortex and striatum of R6/2 mice. Similar results were also found in 2 other mouse models of Huntington's disease and in Huntington's disease patients. Moreover, the interaction and expression levels of potassium‐chloride cotransporter‐2 and its activator (brain‐type creatine kinase) were decreased in Huntington's disease neurons. These findings collectively suggest impaired chloride homeostasis, which further dampens GABAA receptor‐mediated inhibitory signaling in Huntington's disease brains.Conclusions: The dysregulated GABAergic responses and altered expression levels of GABAA receptors and potassium‐chloride cotransporter‐2 in Huntington's disease mice appear to be authentic and may contribute to the clinical manifestations of Huntington's disease patients. © 2017 International Parkinson and Movement Disorder Society