Spectrin-beta 2 facilitates the selective accumulation of GABA(A) receptors at somatodendritic synapses

Fast synaptic inhibition is dependent on targeting specific GABA(A)R subtypes to dendritic and axon initial segment (AIS) synapses. Synaptic GABA(A)Rs are typically assembled from α1-3, β and γ subunits. Here, we isolate distinct GABA(A)Rs 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(A)Rs 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(A)Rs at dendritic synapses, while β4-spectrin was associated with α2-containing GABA(A)Rs 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(A)Rs, determining the efficacy of fast neuronal inhibition.