Spectrin-beta 2 facilitates the selective accumulation of GABA_A receptors at somatodendritic synapses

Fast synaptic inhibition is dependent on targeting specific GABA_AR subtypes to dendritic and axon initial segment (AIS) synapses. Synaptic GABA_ARs are typically assembled from α1-3, β and γ subunits. Here, we isolate distinct GABA_ARs from the brain and interrogate their composition using quantitative proteomics. We show that α2-containing receptors co-assemble with α1 subunits, whereas α1 receptors can form GABA_ARs with α1 as the sole α subunit. We demonstrate that α1 and α2 subunit-containing receptors co-purify with distinct spectrin isoforms; cytoskeletal proteins that link transmembrane proteins to the cytoskeleton. β2-spectrin was preferentially associated with α1-containing GABA_ARs at dendritic synapses, while β4-spectrin was associated with α2-containing GABA_ARs at AIS synapses. Ablating β2-spectrin expression reduced dendritic and AIS synapses containing α1 but increased the number of synapses containing α2, which altered phasic inhibition. Thus, we demonstrate a role for spectrins in the synapse-specific targeting of GABA_ARs, determining the efficacy of fast neuronal inhibition.