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.