Distinct Neurexin-Cerebellin Complexes Control AMPA-and NMDA-Receptor Responses in a Circuit-Dependent Manner

At mature CA1[->]subiculum synapses, alternatively spliced SS4+ variants of neurexin-1 (Nrxn1SS4+) and neurexin-3 (Nrxn3SS4+) enhance NMDA- and suppress AMPA-receptors, respectively. Both Nrxn1SS4+ and Nrxn3SS4+ act by binding to secreted cerebellin-2 (Cbln2) that in turn activates postsynaptic GluD1, which is homologous to AMPA- and NMDA-receptors. Whether neurexin-Cbln2-GluD1 signaling complexes have additional functions in synapse formation besides regulating NMDA- and AMPA-receptors, and whether they perform similar roles at other synapses, remains unknown. Using constitutive Cbln2 deletions, we here demonstrate that at CA1[->]subiculum synapses, Cbln2 performs no additional developmental functions besides regulating AMPA- and NMDA-receptors. Moreover, we show that low-level expression of Cbln1, which is functionally redundant with Cbln2, does not compensate for a synapse-formation function of Cbln2 at CA1[->]subiculum synapses. In exploring the generality of these findings, we found that in prefrontal cortex, Nrxn1SS4+-Cbln2 signaling selectively regulates NMDA-receptors, whereas Nrxn3SS4+-Cbln2 signaling has no apparent role. In contrast, in the cerebellum Nrxn3SS4+-Cbln1 signaling regulates AMPA-receptors, whereas now Nrxn1SS4+-Cbln1 signaling has no manifest effect. Thus, Nrxn1SS4+- and Nrxn3SS4+-Cbln1/2 signaling complexes generally control NMDA- and AMPA-receptors in different synapses without regulating synapse formation, but these signaling complexes are differentially active in diverse neural circuits.