GIT1 and βPIX are essential for GABA(A) receptor synaptic stability and inhibitory neurotransmission

Katharine R Smith, Elizabeth C Davenport, Jing Wei, Xiangning Li, Manavendra Pathania, Victoria Vaccaro, Zhen Yan, Josef T Kittler

Research output: Contribution to journalArticlepeer-review

Abstract

Effective inhibitory synaptic transmission requires efficient stabilization of GABA(A) receptors (GABA(A)Rs) at synapses, which is essential for maintaining the correct excitatory-inhibitory balance in the brain. However, the signaling mechanisms that locally regulate synaptic GABA(A)R membrane dynamics remain poorly understood. Using a combination of molecular, imaging, and electrophysiological approaches, we delineate a GIT1/βPIX/Rac1/PAK signaling pathway that modulates F-actin and is important for maintaining surface GABA(A)R levels, inhibitory synapse integrity, and synapse strength. We show that GIT1 and βPIX are required for synaptic GABA(A)R surface stability through the activity of the GTPase Rac1 and downstream effector PAK. Manipulating this pathway using RNAi, dominant-negative and pharmacological approaches leads to a disruption of GABA(A)R clustering and decrease in the strength of synaptic inhibition. Thus, the GIT1/βPIX/Rac1/PAK pathway plays a crucial role in regulating GABA(A)R synaptic stability and hence inhibitory synaptic transmission with important implications for inhibitory plasticity and information processing in the brain.

Original languageEnglish
Pages (from-to)298-310
Number of pages13
JournalCell Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 9 Oct 2014

Fingerprint

Dive into the research topics of 'GIT1 and βPIX are essential for GABA(A) receptor synaptic stability and inhibitory neurotransmission'. Together they form a unique fingerprint.

Cite this