Identification of a Core Amino Acid Motif within the α Subunit of GABAARs that Promotes Inhibitory Synaptogenesis and Resilience to Seizures

The fidelity of inhibitory neurotransmission is dependent on the accumulation of gamma-aminobutyric acid type A receptors (GABA(A)Rs) at the appropriate synaptic sites. Synaptic GABA(A)Rs are constructed from alpha(1-3), beta(1-3), and gamma 2 subunits, and neurons can target these subtypes to specific synapses. Here, we identify a 15-amino acid inhibitory synapse targeting motif (ISTM) within the alpha 2 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 alpha 1 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 alpha 2 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.