GABA and astrocytic cholesterol determine the lipid environment of GABAR in cultured cortical neurons.

The γ-aminobutyric acid (GABA) type A receptor (GABAR), a GABA activated pentameric chloride channel, mediates fast inhibitory neurotransmission in the brain. The lipid environment is critical for GABAR function. How lipids regulate the channel in the cell membrane is not fully understood. Here we employed super resolution imaging of lipids to demonstrate that the agonist GABA induces a rapid and reversible membrane translocation of GABAR to phosphatidylinositol 4,5-bisphosphate (PIP) clusters in mouse primary cortical neurons. This translocation relies on nanoscopic separation of PIP clusters and lipid rafts (cholesterol-dependent ganglioside clusters). In a resting state, the GABAR associates with lipid rafts and this colocalization is enhanced by uptake of astrocytic secretions. These astrocytic secretions enhance endocytosis and delay desensitization. Our findings suggest intercellular signaling from astrocytes regulates GABAR location based on lipid uptake in neurons. The findings have implications for treating mood disorders associated with altered neural excitability.