Nano-Organization at the Synapse: Segregation of Distinct Forms of Neurotransmission

Abstract

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.

Keywords: asynchronous neurotransmission; nanocolumn; spontaneous neurotransmission; synaptic transmission and plasticity; synchronous neurotransmission.

FIGURE 1

This figure depicts the different modes of neurotransmission and their distinct downstream signaling pathways. Synchronous release transmits precise timing information across the synapse enabling information transfer with fidelity, whereas asynchronous release is thought to regulate short term plasticity and oscillatory activity. In contrast, spontaneous release is action potential independent although it may rely on alternative calcium sources, such as endoplasmic reticulum (ER) mediated calcium via ryanodine receptors (RyR) or store-operated calcium entry via Orai channels activated by the ER calcium sensor STIM. Spontaneous release is thought to play a role in synapse development as well as homeostatic synaptic scaling shaping synaptic efficacy.

FIGURE 2

This figure depicts the nanostructure that is proposed to privilege different modes of release at the synapse, with evoked release supported by specific structural elements (i.e., neurexin and LRRTM2). When viewing the synapse from above one proposal states that evoked release is clustered in confined areas, while asynchronous release is clustered toward the center and spontaneous release is distributed over a larger area of the synapse. Potential plasticity processes may alter nanostructure with increased spine size and a parallel increase in nano-modules as well as increased postsynaptic scaffold and receptor density within nanocolumns.