The synaptic vesicle cluster as a controller of pre- and postsynaptic structure and function

Abstract

The synaptic vesicle cluster (SVC) is an essential component of chemical synapses, which provides neurotransmitter-loaded vesicles during synaptic activity, at the same time as also controlling the local concentrations of numerous exo- and endocytosis cofactors. In addition, the SVC hosts molecules that participate in other aspects of synaptic function, from cytoskeletal components to adhesion proteins, and affects the location and function of organelles such as mitochondria and the endoplasmic reticulum. We argue here that these features extend the functional involvement of the SVC in synapse formation, signalling and plasticity, as well as synapse stabilization and metabolism. We also propose that changes in the size of the SVC coalesce with changes in the postsynaptic compartment, supporting the interplay between pre- and postsynaptic dynamics. Thereby, the SVC could be seen as an 'all-in-one' regulator of synaptic structure and function, which should be investigated in more detail, to reveal molecular mechanisms that control synaptic function and heterogeneity.

Keywords: synapse; synapse formation; synaptic plasticity; synaptic vesicle cluster; vesicle.

Figure 1. Expression of genes encoding for synaptic vesicle proteins in different cell types in the mouse cortex and hippocampus, highlighting the possibility that the synaptic vesicle cluster proteome exhibits molecular diversity between neuronal subtypes

A, in this heatmap, the rows represent genes corresponding to synaptic vesicle proteins identified in a synaptic vesicle fraction of the mouse brain by mass spectrometric analysis. Columns represent hierarchical cell types annotated in the single‐cell Mouse Whole Cortex and Hippocampus 10x dataset from the Allen Brain Map (https://portal.brain‐map.org). The cells contain the averaged expression levels of these genes in the Mouse Whole Cortex and Hippocampus 10x dataset. The heatmap displayed clear clustering patterns among cell types and genes. Genes were clustered based on their average expressions in the cell types using k‐means clustering into five groups. The left colour column shows the clustering results as a coloured column on the left side of the heatmap (clusters 0–4, blue, orange, green, red and purple). B, the top 10 pathways for gene sets in each of the five identified clusters of synaptic proteins. Enrichment analysis was conducted using gene set enrichment analysis and the standard databases ‘KEGG_2019_Mouse’, ‘GO_Molecular_Function_2023’ and ‘GO_Biological_Process_2023’, with the average abundance of the genes in the synaptic protein list serving as the score (Hendriks et al., 2018).

Figure 2. Schematic representation of processes and mechanisms by which the SVC regulates various aspects of synaptic physiology

Top: overview of different steps in synaptic function, from contact initialization to synaptic turnover. The zoomed‐in views indicate the following: (I) Synapse initialization, for which the flow of proto‐SVs is essential because it brings the different adhesion proteins and scaffolds to the location of the future synapse. (II) During synapse maturation, SVC dynamics regulate the size and the initial organization of the synapse. (III) The SVC controls synaptic function, by co‐ordinating the location and activity of different organelles, including the ER and mitochondria, and by regulating processes as exo‐ and endocytosis and cytoskeletal dynamics. (IV) Synapse plasticity is influenced by the SVC, through the removal and/or addition of elements such as SVs and adhesion proteins. (V) The stabilization of a synapse, or its removal, depends on the SVC interaction with brain components such as the ECM or glia.