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.