Figure 10. Working model for the role of MDGAs in excitatory synapse differentiation.

Since NRXNs and MDGAs compete for the binding to NLGN1, the MDGA concentration acts as a key regulator of the signaling events downstream of the NRXN-NLGN1 interaction. When the MDGA level is low in response to KD or KO (right panels), the preferential interaction of NLGN1 with NRXN favors NLGN1 tyrosine phosphorylation and the associated development of excitatory synapses containing AMPARs. When the MDGA level is high (left panel), the NRXN-NLGN1 interaction is weakened and the formation of excitatory synapses is delayed. In dissociated neurons, MDGAs primarily regulate the overall density of NLGN1 and AMPAR modules, but not the actual amount of these molecules at individual synapses (arrow ‘synaptogenesis’). In organotypic slices, MDGAs tend to keep synapses in a silent state with low amounts of AMPARs, and single-cell KO of either MDGA1 or MDGA2 in CA1 neurons promotes the selective recruitment of AMPARs (arrow ‘unsilencing’).