Neurexin-2 restricts synapse numbers and restrains the presynaptic release probability by an alternative splicing-dependent mechanism

a- and (3-neurexins are extensively alternatively spliced, presynaptic cell-adhesion mole-cules that are thought to organize synapse assembly. However, recent data revealed that, in the hippocampus in vivo, the deletion of one neurexin isoform, Nrxn2, surprisingly increased excitatory synapse numbers and enhanced their presynaptic release probabil-ity, suggesting that Nrxn2 restricts, instead of enabling, synapse assembly. To delin-eate the synaptic function and mechanism of action of Nrxn2, we examined cultured hippocampal neurons as a reduced system. In heterologous synapse formation assays, different alternatively spliced Nrxn2(3 isoforms robustly promoted synapse assembly similar to Nrxn1(3 and Nrxn3(3, consistent with a general synaptogenic function of neurexins. Deletion of Nrxn2 from cultured hippocampal neurons, however, caused a significant increase in synapse density and release probability, replicating the in vivo data that suggested a synapse-restricting function. Rescue experiments revealed that two of the four Nrxn2(3 splice variants (Nrxn2(3-SS4+/SS5- and Nrxn2(3-SS4+/SS5+) reversed the increase in synapse density in Nrxn2-deficient neurons, whereas only one of the four Nrxn2(3 splice variants (Nrxn2(3-SS4+/SS5+) normalized the increase in release probability in Nrxn2-deficient neurons. Thus, a subset of Nrxn2 splice variants restricts synapse numbers and restrains their release probability in cultured neurons.

Automated summary

Recent research has shown that the deletion of Nrxn2 unexpectedly leads to an increase in excitatory synapse numbers and their presynaptic release probability, suggesting a role of Nrxn2 in restricting synapse assembly. Cultured hippocampal neurons have been used to study the synaptic function and mechanism of Nrxn2, revealing that certain splice variants of Nrxn2 restrict synapse numbers and restrain their release probability. These findings are significant for understanding the mechanism of synapse assembly.