Abstract
Diverse signaling complexes are precisely assembled at the presynaptic active zone for dynamic modulation of synaptic transmission and synaptic plasticity. Presynaptic GABAB-receptors nucleate critical signaling complexes regulating neurotransmitter release at most synapses. However, the molecular mechanisms underlying assembly of GABAB-receptor signaling complexes remain unclear. Here we show that neurexins are required for the localization and function of presynaptic GABAB-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 GABAB-receptor activation. Moreover, deletion of neurexins caused a loss of GABAB-receptors from the presynaptic active zone of the calyx synapse. These findings extend the role of neurexins at the presynaptic active zone to enabling GABAB-receptor signaling, supporting the notion that neurexins function as central organizers of active zone signaling complexes.
Highlights
Diverse signaling complexes are precisely assembled at the presynaptic active zone for dynamic modulation of synaptic transmission and synaptic plasticity
Action potential-evoked neurotransmitter release occurs with high speed and precision at the presynaptic active zone, which is tightly organized at the nanometer level in the nerve terminal
To analyze the potential role of neurexins in organizing presynaptic GABAB-receptors, we first studied the calyx of Held, a giant glutamatergic synapse in the medial nucleus of the trapezoid body (MNTB)[35,36,37]
Summary
Diverse signaling complexes are precisely assembled at the presynaptic active zone for dynamic modulation of synaptic transmission and synaptic plasticity. Studies have revealed that every aspect of active zone functions is mediated by evolutionarily conserved scaffolding molecules, including RIMs, RIM-binding proteins, ELKS/Bruchpilot, and Munc[132–8] These molecules interact with each other and other signaling proteins to determine the number of Ca2+-channels and their spatial coupling with primed synaptic vesicles, both of which are critical for determining the release probability of a synapse[2,3,6,8]. The expression, distribution, and functional properties of Ca2+-channels at the presynaptic active zone are extensively modulated by diverse G-protein coupled receptors (GPCRs)[9,10,11] This modulation greatly enhances the power of synaptic computations in various forms of short-term and long-term plasticity[12]. It remains unclear how the complex is formed and regulated
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