In the brain, many types of interneurons make functionally diverse inhibitory synapses onto principal neurons. Although numerous molecules have been identified to function in inhibitory synapse development, it remains unknown whether there is a unifying mechanism for development of diverse inhibitory synapses. Here we report a general molecular mechanism underlying hippocampal inhibitory synapse development. In developing neurons, the establishment of GABAergic transmission depends on Neuroligin 2 (NL2), a synaptic cell adhesion molecule (CAM). During maturation, inhibitory synapse development requires both NL2 and Slitrk3 (ST3), another CAM. Importantly, NL2 and ST3 interact with nanomolar affinity through their extracellular domains to synergistically promote synapse development. Selective perturbation of the NL2-ST3 interaction impairs inhibitory synapse development with consequent disruptions in hippocampal network activity and increased seizure susceptibility. Our findings reveal how unique postsynaptic CAMs work in concert to control synaptogenesis and establish a general framework for GABAergic synapse development.

中文翻译：

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Neuroligin 2和Slitrk3的分子解剖揭示了GABA能突触发展的基本框架。

在大脑中，许多类型的中间神经元在主要神经元上产生功能多样的抑制性突触。尽管已鉴定出许多分子在抑制性突触的发展中发挥作用，但尚不清楚是否存在统一的机制来抑制多种抑制性突触的发展。在这里，我们报告了海马抑制突触发展的一般分子机制。在发育中的神经元中，GABA能传递的建立取决于Neuroligin 2（NL2），一种突触细胞粘附分子（CAM）。在成熟过程中，抑制性突触的形成需要另一种CAM NL2和Slitrk3（ST3）。重要的是，NL2和ST3通过其胞外域与纳摩尔的亲和力相互作用，以协同促进突触的发展。NL2-ST3相互作用的选择性扰动损害了抑制性突触的发展，进而破坏了海马网络的活动并增加了癫痫发作的易感性。我们的研究结果揭示了独特的突触后CAM如何协同工作以控制突触发生并建立GABA能突触发展的一般框架。