In vivo nanoscopic landscape of neurexin ligands underlying anterograde synapse specification

Excitatory synapses are formed and matured by the cooperative actions of synaptic organizers, such as neu-rexins (Nrxns), neuroligins (Nlgns), LRRTMs, and Cbln1. Recent super-resolution nanoscopy developments have revealed that many synaptic organizers, as well as glutamate receptors and glutamate release machin-ery, exist as nanoclusters within synapses. However, it is unclear how such nanodomains interact with each other to organize excitatory synapses in vivo. By applying X10 expansion microscopy to epitope tag knockin mice, we found that Cbln1, Nlgn1, and LRRTM1, which share Nrxn as a common presynaptic receptor, form overlapping or separate nanodomains depending on Nrxn with or without a sequence encoded by splice site 4. The size and position of glutamate receptor nanodomains of GluD1, NMDA, and AMPA receptors were regulated by Cbln1, Nlgn1, and LRRTM1 nanodomains, respectively. These findings indicate that Nrxns anterogradely regulate the postsynaptic nanoscopic architecture of glutamate receptors through competi-tion and coordination of Nrxn ligands.

Automated summary

Excitatory synapses are formed and matured by the cooperative actions of various synaptic organizers, and recent super-resolution nanoscopy developments have revealed the existence of nanoclusters within synapses. These nanodomains interact with each other to organize excitatory synapses, with Nrxns regulating the postsynaptic nanoscopic architecture of glutamate receptors through competition and coordination of Nrxn ligands.