Neurexins regulate presynaptic GABA(B)-receptors at central synapses.

Diverse signaling complexes are precisely assembled at the presynaptic active zone for dynamic modulation of synaptic transmission and synaptic plasticity. Presynaptic GABA(B)-receptors nucleate critical signaling complexes regulating neurotransmitter release at most synapses. However, the molecular mechanisms underlying assembly of GABA(B)-receptor signaling complexes remain unclear. Here we show that neurexins are required for the localization and function of presynaptic GABA(B)-receptor signaling complexes. At four model synapses, excitatory calyx of Held synapses in the brainstem, excitatory and inhibitory synapses on hippocampal CA1-region pyramidal neurons, and inhibitory basket cell synapses in the cerebellum, deletion of neurexins rendered neurotransmitter release significantly less sensitive to GABA(B)-receptor activation. Moreover, deletion of neurexins caused a loss of GABA(B)-receptors from the presynaptic active zone of the calyx synapse. These findings extend the role of neurexins at the presynaptic active zone to enabling GABA(B)-receptor signaling, supporting the notion that neurexins function as central organizers of active zone signaling complexes.