Differential dynamics and activity-dependent regulation of α- and β-neurexins at developing GABAergic synapses

Neurexins (NRXs) and neuroligins are key synaptic adhesion molecules that also recruit synaptic signaling machineries. Neurexins consist of alpha- and beta-isoforms, but how they couple synaptic transmission and adhesion to regulate activity-dependent synapse development remains unclear, in part because of poor understanding of their cell biology and regulation in the relevant neurons. Here, we examined the subaxonal localization, dynamics, and regulation of NRX1 alpha and NRX1 beta in cortical perisomatic inhibitory synapses. Both isoforms are delivered to presynaptic terminals but show significant and different turnover rate at the membrane. Although NRX1 alpha is highly diffuse along developing axons and filopodia, NRX1 beta is strictly anchored at terminals through binding to postsynaptic ligands. The turnover rate of NRX1 beta is attenuated by neural activity and presynaptic GABA(B) receptors. NRXs, thus, are intrinsically dynamic but are stabilized by local transmitter release. Such an activity-adjusted adhesion system seems ideally suited to rapidly explore and validate synaptic partners guided by synaptic transmission.