Synapses maintain synchronous, asynchronous, and spontaneous modes of neurotransmission through distinct molecular and biochemical pathways. Traditionally a single synapse was assumed to have a homogeneous organization of molecular components both at the active zone and post-synaptically. However, recent advancements in experimental tools and the further elucidation of the physiological significance of distinct forms of release have challenged this notion. In comparison to rapid evoked release, the physiological significance of both spontaneous and asynchronous neurotransmission has only recently been considered in parallel with synaptic structural organization. Active zone nanostructure aligns with postsynaptic nanostructure creating a precise trans-synaptic alignment of release sites and receptors shaping synaptic efficacy, determining neurotransmission reliability, and tuning plasticity. This review will discuss how studies delineating synaptic nanostructure create a picture of a molecularly heterogeneous active zone tuned to distinct forms of release that may dictate diverse synaptic functional outputs.

SUMMARY Inhibition of neurotransmitter release by neurotransmitter substances constitutes a fundamental means of neuromodulation. In contrast to well-delineated mechanisms that underlie inhibition of evoked release via suppression of voltage-gated Ca 2+ channels, processes that underlie neuromodulatory inhibition of spontaneous release remain unclear. Here, we interrogated inhibition of spontaneous glutamate and GABA release by presynaptic metabotropic GABA B receptors. Our findings show that this inhibition relies on Gβγ subunit action at the membrane, and it is largely independent of presynaptic Ca 2+ signaling for both forms of release. In the case of spontaneous glutamate release, inhibition requires Gβγ interaction with the C terminus of the key fusion machinery component SNAP25, and it is modulated by synaptotagmin-1. Inhibition of spontaneous GABA release, on the other hand, is independent of these pathways and likely requires alternative Gβγ targets at the presynaptic terminal.

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