کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
6022623 | 1580683 | 2012 | 6 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Disrupted GABAAR trafficking and synaptic inhibition in a mouse model of Huntington's disease Disrupted GABAAR trafficking and synaptic inhibition in a mouse model of Huntington's disease](/preview/png/6022623.png)
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. GABAA 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 GABAA receptors to the kinesin family motor protein 5 (KIF5), controlling the transport of GABAA receptors along microtubules in dendrites. In this study, we found that GABAAR-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 GABAA receptors. Moreover, the GABAAR/HAP1/KIF5 complex is disrupted and dissociated from microtubules in the HD mouse model. These results suggest that GABAAR trafficking and function is impaired in HD, presumably due to the interference of KIF5-mediated microtubule-based transport of GABAA receptors. The diminished inhibitory synaptic efficacy could contribute to the loss of the excitatory/inhibitory balance, leading to increased neuronal excitotoxicity in HD.
⺠We compared synaptic inhibition in wild-type and a transgenic mouse model of HD. ⺠We examined GABAA receptor surface expression in the HD mouse model. ⺠We examined the GABAAR/KIF5/microtubule complex in the HD mouse model. ⺠We find that GABAAR-mediated synaptic inhibition is impaired in HD. ⺠We find that KIF5-mediated microtubule-based transport of GABAARs is disturbed in HD.
Journal: Neurobiology of Disease - Volume 46, Issue 2, May 2012, Pages 497-502