GABA and astrocytic cholesterol determine the lipid environment of GABA(A)R in cultured cortical neurons.

The γ-aminobutyric acid (GABA) type A receptor (GABA(A)R), a GABA activated pentameric chloride channel, mediates fast inhibitory neurotransmission in the brain. The lipid environment is critical for GABA(A)R 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 GABA(A)R to phosphatidylinositol 4,5-bisphosphate (PIP(2)) clusters in mouse primary cortical neurons. This translocation relies on nanoscopic separation of PIP(2) clusters and lipid rafts (cholesterol-dependent ganglioside clusters). In a resting state, the GABA(A)R associates with lipid rafts and this colocalization is enhanced by uptake of astrocytic secretions. These astrocytic secretions delay desensitization and enhance maximum current. In an Alzheimer's Disease (AD) mouse model with high brain cholesterol, GABA(A)R shifts into lipid rafts. Our findings suggest cholesterol is a signaling molecule and astrocytes regulates GABA(A)Rs in neurons by secreting cholesterol. The findings have implications for treating mood disorders and AD associated with altered brain lipids.