The fidelity of inhibitory neurotransmission is dependent on the accumulation of γ-aminobutyric acid type A receptors (GABA_ARs) at the appropriate synaptic sites. Synaptic GABA_ARs 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_ARs 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.

抑制性神经传递的保真度取决于γ-氨基丁酸_A型受体（GABA _A Rs）在适当的突触位点的积累。突触的GABA _A Rs由α（1-3），β（1-3）和γ2亚基构成，神经元可以将这些亚型靶向特定的突触。在这里，我们确定了α2亚基内的一个15个氨基酸的抑制突触靶向基序（ISTM），该基序可促进GABA _A Rs与抑制性支架蛋白Collbisintin和gephyrin之间的关联。使用其中将ISTM引入α1亚基的小鼠（Gabra 1-2小鼠），我们证明了ISTM对于轴突-突触突触形成，GABA能神经传递的功效和癫痫发作敏感性至关重要。这Gabra 1-2突变挽救了Gabra 2-1小鼠的癫痫发作致死性，该小鼠缺乏轴突-轴突突触，这是由于ISTM从α2亚基中缺失所致。两者合计，我们的数据表明ISTM在促进轴突和躯体树突区室的抑制性突触形成中起关键作用。