Disrupted GABA _AR trafficking and synaptic inhibition in a mouse model of Huntington's disease

Growing evidence suggests that Huntington's disease (HD), a neurodegenerative movement disorder caused by the mutant huntingtin (htt) with an expanded polyglutamine (polyQ) repeat, is associated with the altered intracellular trafficking and synaptic function. GABA _A receptors, the key determinant of the strength of synaptic inhibition, have been found to bind to the huntingtin associated protein 1 (HAP1). HAP1 serves as an adaptor linking GABA _A receptors to the kinesin family motor protein 5 (KIF5), controlling the transport of GABA _A receptors along microtubules in dendrites. In this study, we found that GABA _AR-mediated synaptic transmission is significantly impaired in a transgenic mouse model of HD expressing polyQ-htt, which is accompanied by the diminished surface expression of GABA _A receptors. Moreover, the GABA _AR/HAP1/KIF5 complex is disrupted and dissociated from microtubules in the HD mouse model. These results suggest that GABA _AR trafficking and function is impaired in HD, presumably due to the interference of KIF5-mediated microtubule-based transport of GABA _A receptors. The diminished inhibitory synaptic efficacy could contribute to the loss of the excitatory/inhibitory balance, leading to increased neuronal excitotoxicity in HD.