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

详细信息	查看全文 | 推荐本文 |

• 作者：Eunice Y. Yuen¹ ; Jing Wei¹ ; Ping Zhong ; Zhen Yan ; ^{zhenyan@buffalo.edu}
• 关键词：Huntingtin ; GABAA receptor ; IPSC ; KIF5 ; Microtubule ; Trafficking
• 刊名：Neurobiology of Disease
• 出版年：2012
• 期刊代码：80_09699961
• 类别：neu
• 出版时间：May, 2012
• 卷：46
• 期：2
• 页码：497-502
• 文件大小：711 K

摘要

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.