LAUSR

Significance Previous in vivo studies showed that neurexin-2 unexpectedly regulates synaptic connectivity in hippocampal circuits not by inducing, but by repressing excitatory synapses. The present study demonstrates that as assessed by heterologous synapse formation experiments, a commonly used in vitro synaptogenesis assay, neurexin-2 powerfully induces synapse formation. However, neurexin-2 deletions nevertheless increased the number and the release probability of synapses in cultured hippocampal neurons, indicating a synapse-restricting function consistent with the in vivo results. Rescue experiments revealed that the two phenotypes of the neurexin-2 deletion were differentially reversed by distinct combinations of neurexin-2βsplice variants, suggesting a dual restrictive mechanism of neurexin-2 in synaptic connectivity that differs from that of other neurexins and that is regulated by alternative splicing of neurexin-2.