Identification of a Core Amino Acid Motif within the α Subunit of GABA(A)Rs that Promotes Inhibitory Synaptogenesis and Resilience to Seizures

SUMMARY: The fidelity of inhibitory neurotransmission is dependent on the accumulation of γ-aminobutyric acid type A receptors (GABA(A)Rs) at the appropriate synaptic sites. Synaptic GABA(A)Rs are constructed from α(1–3), β(1–3), and γ2 subunits, and neurons can target these subtypes to specific synapses. Here, we identify a 15-amino acid inhibitory synapse targeting motif (ISTM) within the α2 subunit that promotes the association between GABA(A)Rs and the inhibitory scaffold proteins collybistin and gephyrin. Using mice in which the ISTM has been introduced into the α1 subunit (Gabra1–2 mice), we show that the ISTM is critical for axo-axonic synapse formation, the efficacy of GABAergic neurotransmission, and seizure sensitivity. The Gabra1–2 mutation rescues seizure-induced lethality in Gabra2–1 mice, which lack axo-axonic synapses due to the deletion of the ISTM from the α2 subunit. Taken together, our data demonstrate that the ISTM plays a critical role in promoting inhibitory synapse formation, both in the axonic and somatodendritic compartments. IN BRIEF: Molecular mechanisms regulating specific synaptic GABA(A)R accumulation are critical for the fidelity of inhibitory neurotransmission. Nathanson et al. show that strengthening the interaction between α1-GABA(A)Rs and collybistin via genetic manipulation results in augmented synaptic targeting of these receptors, enhanced inhibitory neurotransmission, and seizure resilience.