Transsynaptic Signaling by Activity-Dependent Cleavage of Neuroligin-1

Adhesive contact between pre- and postsynaptic neurons initiates synapse formation during brain development and provides a natural means of transsynaptic signaling. Numerous adhesion molecules and their role during synapse development have been described in detail. However, once established, the mechanisms of adhesive disassembly and its function in regulating synaptic transmission have been unclear. Here, we report that synaptic activity induces acute proteolytic cleavage of neuroligin-1 (NLG1), a postsynaptic adhesion molecule at glutamatergic synapses. NLG1 cleavage is triggered by NMDA receptor activation, requires Ca2+/calmodulin-dependent protein kinase, and is mediated by proteolytic activity of matrix metalloprotease 9 (MMP9). Cleavage of NLG1 occurs at single activated spines, is regulated by neural activity in vivo, and causes rapid destabilization of its presynaptic partner neurexin-1β (NRX1β). In turn, NLG1 cleavage depresses synaptic transmission by abruptly reducing presynaptic release probability. Thus, local proteolytic control of synaptic adhesion tunes synaptic transmission during brain development and plasticity. ► Synaptic activity triggers loss of neuroligin-1 ► Matrix metalloprotease-9 cleaves neuroligin-1 in an NMDAR/CaMK-dependent pathway ► Cleavage of NLG1 destabilizes neurexin-1b and acutely decreases glutamate release ► Neuroligin-1 cleavage is induced by seizures and sensory experience in vivo Neuroligin-1 is a postsynaptic adhesion protein at glutamatergic synapses. Peixoto et al. report that synaptic activity triggers cleavage of neuroligin-1 by matrix metalloprotease-9, resulting in reduced presynaptic neurotransmitter release.