The subsynaptic organization of postsynaptic neurotransmitter receptors into nanoclusters that are aligned with presynaptic release sites is essential for the high fidelity of synaptic transmission. However, the mechanisms controlling the nanoscale organization of neurotransmitter receptors in vivo remain incompletely understood. Here, we deconstructed the role of neuroligin-3 (Nlgn3), a postsynaptic adhesion molecule linked to autism, in organizing AMPA-type glutamate receptors in the calyx of Held synapse. Deletion of Nlgn3 lowered the amplitude and slowed the kinetics of AMPA receptor–mediated synaptic responses. Super-resolution microscopy revealed that, unexpectedly, these impairments in synaptic transmission were associated with an increase in the size of postsynaptic PSD-95 and AMPA receptor nanoclusters but a decrease of the densities in these clusters. Modeling showed that a dilution of AMPA receptors into larger nanocluster volumes decreases synaptic strength. Nlgn3, likely by binding to presynaptic neurexins, thus is a key organizer of AMPA receptor nanoclusters that likely acts via PSD-95 adaptors to optimize the fidelity of synaptic transmission.

中文翻译：

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Neuroligin-3 将 AMPA 受体限制在纳米簇中，从而控制 Held 突触花萼处的突触强度


突触后神经递质受体的突触亚组织形成与突触前释放位点对齐的纳米簇对于突触传递的高保真度至关重要。然而，控制体内神经递质受体纳米级组织的机制仍不完全清楚。在这里，我们解构了 Neuroligin-3 (Nlgn3)（一种与自闭症相关的突触后粘附分子）在组织 Held 突触花萼中的 AMPA 型谷氨酸受体中的作用。删除NLGN3降低了 AMPA 受体介导的突触反应的幅度并减慢了动力学。超分辨率显微镜意外地发现，突触传递的这些损伤与突触后 PSD-95 和 AMPA 受体纳米簇尺寸的增加有关，但这些簇的密度却降低了。建模表明，将 AMPA 受体稀释成更大的纳米簇体积会降低突触强度。 Nlgn3 可能通过与突触前神经毒素结合，因此是 AMPA 受体纳米簇的关键组织者，可能通过 PSD-95 适配器发挥作用，以优化突触传递的保真度。