GM1 GANGLIOSIDES DIRECTLY BIND GABA<SUB>A</SUB> RECEPTORS TO TUNE INHIBITORY SYNAPSE PLASTICITY

Type A GABA receptors (GABA_ARs) mediate inhibitory transmission in the central nervous system. Reduced GABAergic inhibition, leading to neuronal hyperactivity, is a hallmark of several neurological disorders, including epilepsy. Synaptic GABA_AR number critically determines inhibitory efficacy and plasticity, yet the mechanisms regulating their synaptic localization remain incompletely understood.
GABA_ARs are enriched in lipid rafts, specialized membrane domains containing gangliosides such as GM1. Reduced GM1 levels have been reported in epileptic mouse models and human brain tissue. In hippocampal neurons, we found that GM1 forms clusters that colocalize with a subset of synaptic GABA_AR α1 clusters. GM1-positive clusters were larger and displayed higher receptor density, indicating a specific role for GM1 in synaptic GABA_AR organization. Chronic GM1 treatment increased neuronal surface GM1 levels without affecting inhibitory synapses under basal conditions. However, during homeostatic plasticity induced by chronic TTX treatment, GM1 significantly potentiated the loss of synaptic GABA_AR α1 and γ2 subunits. This structural remodeling was accompanied by increased intracellular calcium levels, consistent with weakened inhibitory transmission. The effect was specific to GM1 and selective for α1 and γ2 subunits, without altering channel properties or gephyrin organization. GM1 reduced α1 lateral diffusion and promoted receptor endocytosis. Bioinformatic and biochemical analyses identified direct GM1 binding to ganglioside-binding domains on α1 and γ2 subunits. Mutations disrupting these domains impaired synaptic GABA_AR clustering and abolished GM1-dependent potentiation of homeostatic plasticity. Together, these findings demonstrate that direct GM1-GABA_AR interactions are a new key mechanism for activity-dependent tuning of inhibitory synapses.