Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin

Neuron. 2010 Jan 14;65(1):53-65. doi: 10.1016/j.neuron.2009.12.007.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Humans
  • Huntingtin Protein
  • Huntington Disease / metabolism
  • Kinesin / genetics
  • Kinesin / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / cytology
  • Neurons / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Patch-Clamp Techniques
  • Peptides / genetics
  • Peptides / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism*
  • Synapses / metabolism*
  • Synapses / ultrastructure
  • Synaptic Transmission / physiology

Substances

  • Hap1 protein, rat
  • Htt protein, rat
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • Protein Isoforms
  • Receptors, GABA-A
  • polyglutamine
  • Kif5A protein, rat
  • Kinesin