title: Disrupted GABAAR trafficking and synaptic inhibition in a mouse model of Huntington's disease.
abstract: 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(A)R-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(A)R/HAP1/KIF5 complex is disrupted and dissociated from microtubules in the HD mouse model. These results suggest that GABA(A)R 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.
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA.
authors.forename: Eunice Y
authors.initials: EY
authors.lastname: Yuen
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.forename: Ping
authors.initials: P
authors.lastname: Zhong
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000378:metabolism* / Q000503:physiopathology*; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism; D009433:Neural Inhibition / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D011963:Receptors, GABA-A / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D011963:Receptors, GABA-A