Subsynaptic spatial organization as a regulator of synaptic strength and plasticity

Abstract

Synapses differ markedly in their performance, even amongst those on a single neuron. The mechanisms that drive this functional diversification are of great interest because they enable adaptive behaviors and are targets of pathology. Considerable effort has focused on elucidating mechanisms of plasticity that involve changes to presynaptic release probability and the number of postsynaptic receptors. However, recent work is clarifying that nanoscale organization of the proteins within glutamatergic synapses impacts synapse function. Specifically, active zone scaffold proteins form nanoclusters that define sites of neurotransmitter release, and these sites align transsynaptically with clustered postsynaptic receptors. These nanostructural characteristics raise numerous possibilities for how synaptic plasticity could be expressed.

Nanoscale Subsynaptic Domains Underlie the Organization of the Inhibitory Synapse

“…This arrangement places AMPARs in the optimal position for efficient activation, opposite presynaptic glutamate release sites, and is proposed to be critical for efficient synaptic transmission (Biederer et al, 2017;Haas et al, 2018;MacGillavry et al, 2013;Sinnen et al, 2017;Tang et al, 2016). Moreover, nanoscale alterations to synapse substructure and composition are thought to significantly affect synaptic efficacy and synaptic plasticity (Biederer et al, 2017;Chen et al, 2018;MacGillavry and Hoogenraad, 2015;MacGillavry et al, 2013;Nair et al, 2013;Purkey et al, 2018;Sinnen et al, 2017;Smith et al, 2014b;Tang et al, 2016;Tønnesen et al, 2014). In contrast with excitatory synapses, our understanding of the nanoscale organization of inhibitory synapses remains rudimentary.…”

Differential Scaling of Synaptic Molecules within Functional Zones of an Excitatory Synapse during Homeostatic Plasticity

“…Last three decades of research have shown that the instantaneous distribution of synaptic molecules contributes to both the structure and function of individual synapses (Kandel et al, 2014;Bailey et al, 2015;Sossin, 2018). The spatiotemporal heterogeneity of AMPA type glutamatergic receptors at excitatory synapses have been directly correlated to short term plasticity and activity dependent changes in the synaptic strength (Henley and Wilkinson, 2016;Chen et al, 2018;Humeau and Choquet, 2019). Quantifying the variability in electrophysiological properties of AMPA receptor responses in synapses along with their localization and trafficking have enabled us to understand finer aspects of both basal synaptic transmission and activity dependent changes associated with it (Greger et al, 2017;Diering and Huganir, 2018).…”

“…Though conventional microscopy data has shed light on instantaneous distribution and recycling of receptors in the synapses, it seldom focuses on the properties of individual synapses. Furthermore, advances in high-resolution microscopy in the recent years have enabled researchers to examine variability within individual synapses and map the topology of AMPA receptor distribution within functional zones such as the postsynaptic density and the perisynaptic region of excitatory synapses, spatially separated by few 100 nanometres (Chen et al, 2018;Scheefhals and MacGillavry, 2018;Humeau and Choquet, 2019). Here we have studied the spatial heterogeneity of proteins at synapses using conventional microscopy and calculated their individual scaling factors with a method similar to the one used for electrophysiological recordings (Kim et al, 2012).…”

On the cause of sleep: Protein fragments, the concept of sentinels, and links to epilepsy

“…PSDs are located underneath synapse-encompassing patches of the plasma membrane in dendritic spines of postsynaptic neurons. PSDs are rich in scaffold/cytoskeletal proteins (72)(73)(74)(75)(76)(77)(78)(79)(80)(81). Specific scaffold proteins bind to cytosolic domains of glutamate receptors such as AMPAR, NMDAR, and mGluR1, transiently trapping these and other transmembrane proteins within a PSD (80).…”

“…Gephyrin (GPHN), a postsynaptic scaffold protein in inhibitory synapses, can be cleaved, at a specific site, by activated calpains (88). As to PSDs of excitatory synapses, they contain many calpain substrates, including PSD95, PSD93, PSD97, GRIP1, spectrin (SPTBN1), ezrin (EZR), stargazin (CACGN2), p35 (CDK5R1), and cytosolic domains of PSD-entrapped transmembrane proteins such as NMDAR, AMPAR, mGluR1, and N-cadherin (37,73,74,77). For most of these proteins, specific physiological functions of cleavages by calpains are still unknown.…”