Delivery of GABAARs to Synapses Is Mediated by HAP1-KIF5 and Disrupted by Mutant Huntingtin

SummaryThe density of GABAA receptors (GABAARs) 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 GABAARs to synapses is unknown. We demonstrate that GABAARs 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 GABAAR number and reduces the amplitude of inhibitory postsynaptic currents. When huntingtin is mutated, as in Huntington's disease, GABAAR transport and inhibitory synaptic currents are reduced. Thus, HAP1-KIF5-dependent GABAAR 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.

► Rapid delivery of GABAARs to inhibitory synapses is mediated by the motor KIF5
► Huntingtin-associated protein 1 (HAP1) is the adapter linking GABAARs to KIF5
► Blocking the GABAAR/HAP1/KIF5 complex disrupts inhibitory synaptic transmission
► PolyQ-huntingtin disrupts GABAAR transport and impairs synaptic inhibition