GIT1 and βPIX Are Essential for GABA A Receptor Synaptic Stability and Inhibitory Neurotransmission

Summary Effective inhibitory synaptic transmission requires efficient stabilization of GABAA receptors (GABAARs) at synapses, which is essential for maintaining the correct excitatory-inhibitory balance in the brain. However, the signaling mechanisms that locally regulate synaptic GABAAR 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 GABAAR levels, inhibitory synapse integrity, and synapse strength. We show that GIT1 and βPIX are required for synaptic GABAAR 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 GABAAR clustering and decrease in the strength of synaptic inhibition. Thus, the GIT1/βPIX/Rac1/PAK pathway plays a crucial role in regulating GABAAR synaptic stability and hence inhibitory synaptic transmission with important implications for inhibitory plasticity and information processing in the brain.

Graphical Abstract

Highlights • GIT1 and βPIX are present at inhibitory synapses and complex with GABAARs • GIT1 and βPIX are important for GABAAR clustering and inhibitory transmission • Rac1 and PAK activity is required for stabilization of GABAARs at synapses • A GIT1/βPIX/Rac1/PAK pathway is required for inhibitory synaptic transmission

Clustering of GABAA receptors at inhibitory synapses is important for maintaining the correct balance of excitation and inhibition in the brain. Smith et al. reveal a signaling mechanism at inhibitory synapses involving the scaffold GIT1, which anchors βPIX to the inhibitory synaptic site and activates Rac1 and PAK, thereby stabilizing F-actin. This signaling pathway underlies the stabilization of synaptic GABAA receptors and therefore contributes to efficient inhibitory synaptic transmission in the brain.