Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin.
The density of GABA(A) receptors (GABA(A)Rs) at synapses regulates brain excitability, and altered inhibition may contribute to Huntington's disease, which is caused by a polyglutamine repeat in the protein huntingtin. However, the machinery that delivers GABA(A)Rs to synapses is unknown. We demonstrate that GABA(A)Rs are trafficked to synapses by the kinesin family motor protein 5 (KIF5). We identify the adaptor linking the receptors to KIF5 as the huntingtin-associated protein 1 (HAP1). Disrupting the HAP1-KIF5 complex decreases synaptic GABA(A)R number and reduces the amplitude of inhibitory postsynaptic currents. When huntingtin is mutated, as in Huntington's disease, GABA(A)R transport and inhibitory synaptic currents are reduced. Thus, HAP1-KIF5-dependent GABA(A)R trafficking is a fundamental mechanism controlling the strength of synaptic inhibition in the brain. Its disruption by mutant huntingtin may explain some of the defects in brain information processing occurring in Huntington's disease and provides a molecular target for therapeutic approaches.
Department of Neuroscience, Physiology, and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.
Alison E
AE
Twelvetrees
Eunice Y
EY
Yuen
I Lorena
IL
Arancibia-Carcamo
Andrew F
AF
MacAskill
Philippe
P
Rostaing
Michael J
MJ
Lumb
Sandrine
S
Humbert
Antoine
A
Triller
Frederic
F
Saudou
Zhen
Z
Yan
Josef T
JT
Kittler
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000502:physiology
C490757:Hap1 protein, rat; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D020033:Protein Isoforms; D011963:Receptors, GABA-A; C097188:polyglutamine; C547919:Kif5A protein, rat; D016547:Kinesins