GIT1 and βPIX are essential for GABA_A receptor synaptic stability and inhibitory neurotransmission

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