Correlative Assembly of Subsynaptic Nanoscale Organizations During Development

Sun, Shiyan; Li, Xiaowei; Cao, Ran; Zhao, Yang; Sheng, Nengyin; Tang, Aohan

doi:10.3389/fnsyn.2022.748184

Cited by 13 publications

(16 citation statements)

References 62 publications

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“…4F, right) and area (Table 4-1; Fig. 4G, right) of PSD-95 NCs increased substantially after the first week, similar to what has been observed previously (Sun et al, 2022). Additionally, PSD-95 Δdensity did not change across development for alone or paired synapses (Table 4-1; Fig.…”

Section: Resultssupporting

confidence: 87%

Distinct SAP102 and PSD-95 nano-organization defines multiple types of synaptic scaffold protein domains at single synapses

Metzbower,

Dharmasri,

Levy

et al. 2023

Preprint

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The MAGUK family of scaffold proteins plays a central role in maintaining and modulating synaptic signaling, providing a framework to retain and position receptors, signaling molecules, and other synaptic components. Of these scaffold proteins, SAP102 and PSD-95 are essential for synaptic function at distinct developmental timepoints and perform overlapping as well as unique roles. While their similar structures allow for common binding partners, SAP102 is expressed earlier in synapse development and is required for synaptogenesis, whereas PSD-95 expression peaks later in development and is associated with synapse maturation. PSD-95 and other key synaptic proteins organize into subsynaptic nanodomains that have a significant impact on synaptic transmission, but the nanoscale organization of SAP102 is unknown. How SAP102 is organized within the synapse, and how it relates spatially to PSD-95 on a nanometer scale, could impact how SAP102 clusters synaptic proteins and underlie its ability to perform its unique functions. Here we used DNA-PAINT super-resolution microscopy to measure SAP102 nano-organization and its spatial relationship to PSD-95 at individual synapses. We found that like PSD-95, SAP102 accumulates in high-density subsynaptic nanoclusters. However, SAP102 nanoclusters were smaller and denser than PSD-95 nanoclusters across development. Additionally, only a subset of SAP102 nanoclusters co-organized with PSD-95, revealing that within individual synapses there are nanodomains that contain either one or both proteins. This organization into both shared and distinct subsynaptic nanodomains may underlie the ability of SAP102 and PSD-95 to perform both common and unique synaptic functions.Significance statementSAP102 and PSD-95 are two key members of the MAGUK family of synaptic scaffold proteins that are critical for synapse development, maintenance, and modification during plasticity. Because PSD-95 has a highly complex subsynaptic nanostructure that impacts synaptic function, we asked if SAP102 is similarly organized into nanoclusters at individual synapses and how it relates to PSD-95 within synapses. We found that SAP102 forms subsynaptic nanoclusters with unique properties, and that within individual synapses proteins both concentrate into overlapping nanodomains, as well as form MAGUK-specific nanodomains. This demonstrates that organization of synaptic proteins into nanoclusters is likely to be maintained within the family of MAGUK proteins and reveals potential mechanism for specializing functions within individual synapses based on scaffold protein nanodomains.

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Section: Resultssupporting

confidence: 87%

Distinct SAP102 and PSD-95 nano-organization defines multiple types of synaptic scaffold protein domains at single synapses

Metzbower,

Dharmasri,

Levy

et al. 2023

Preprint

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show abstract

“…Co‐staining with antibodies of two rabbit origins (rabbit anti‐GluA1, ab31232, 1:200; rabbit anti‐RIM1/2) was performed as described. [ 29 ] In brief, staining was performed separately, the first primary antibody (rabbit anti‐GluA1) was blocked and converted with a goat anti‐rabbit Fab fragment (Jackson Immuno, 111‐007‐003, 1:100) for 1.5 h at room temperature. After washing with PBS plus 50‐mM glycine, primary antibodies (rabbit anti‐RIM1/2) were incubated for 3 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Nanoscale reorganisation of synaptic proteins in Alzheimer's disease

Zhu

Yang

Gou

et al. 2023

Neuropathology Appl Neurobio

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AimsSynaptic strength depends strongly on the subsynaptic organisation of presynaptic transmitter release and postsynaptic receptor densities, and their alterations are expected to underlie pathologies. Although synaptic dysfunctions are common pathogenic traits of Alzheimer's disease (AD), it remains unknown whether synaptic protein nano‐organisation is altered in AD.Here, we systematically characterised the alterations in the subsynaptic organisation in cellular and mouse models of AD.MethodsWe used immunostaining and super‐resolution stochastic optical reconstruction microscopy imaging to quantitatively examine the synaptic protein nano‐organisation in both Aβ1–42‐treated neuronal cultures and cortical sections from a mouse model of AD, APP23 mice.ResultsWe found that Aβ1–42‐treatment of cultured hippocampal neurons decreased the synaptic retention of postsynaptic scaffolds and receptors and disrupted their nanoscale alignment to presynaptic transmitter release sites. In cortical sections, we found that while GluA1 receptors in wild‐type mice were organised in subsynaptic nanoclusters with high local densities, receptors in APP23 mice distributed more homogeneously within synapses. This reorganisation, together with the reduced overall receptor density, led to reduced glutamatergic synaptic transmission. Meanwhile, the transsynaptic alignment between presynaptic release‐guiding RIM1/2 and postsynaptic scaffolding protein PSD‐95 was reduced in APP23 mice. Importantly, these reorganisations were progressive with age and were more pronounced in synapses in close vicinity of Aβ plaques with dense cores.ConclusionsOur study revealed a spatiotemporal‐specific reorganisation of synaptic nanostructures in AD and identifies dense‐core amyloid plaques as the major local inductor in APP23 mice.

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“…Here, we document variability in molecular characteristics of presynaptic release sites within a single active zone and show that NMDAR subsynaptic distribution is dependent on highly local transcellular context. Other recent work has shown that postsynapses contain diverse scaffold molecules beyond PSD-95 that are organized in unique and developmentally regulated NCs 10,71,72 . Synaptic nanoclustering and trans-synaptic alignment are conserved in evolution and observed across several synapse types 40,73,74 , the detailed characteristics of which depend on cleftresident synaptic organizing complexes 1,9,11,14 .…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Trans-synaptic molecular context of NMDA receptor nanodomains

Anderson,

Levy,

Dharmasri

et al. 2023

Preprint

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Tight coordination of the spatial relationships between protein complexes is required for cellular function. In neuronal synapses, many proteins responsible for neurotransmission organize into subsynaptic nanoclusters whose trans-cellular alignment modulates synaptic signal propagation. However, the spatial relationships between these proteins and NMDA receptors (NMDARs), which are required for learning and memory, remain undefined. Here, we mapped the relationship of key NMDAR subunits to reference proteins in the active zone and postsynaptic density using multiplexed super-resolution DNA-PAINT microscopy. GluN2A and GluN2B subunits formed nanoclusters with diverse configurations that, surprisingly, were not localized near presynaptic vesicle release sites marked by Munc13-1. However, a subset of presynaptic sites was configured to maintain NMDAR activation: these were internally denser, aligned with abundant PSD-95, and associated closely with specific NMDAR nanodomains. This work reveals a new principle regulating NMDAR signaling and suggests that synaptic functional architecture depends on assembly of multiprotein nanodomains whose interior construction is conditional on trans-cellular relationships.

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Correlative Assembly of Subsynaptic Nanoscale Organizations During Development

Cited by 13 publications

References 62 publications

Distinct SAP102 and PSD-95 nano-organization defines multiple types of synaptic scaffold protein domains at single synapses

Distinct SAP102 and PSD-95 nano-organization defines multiple types of synaptic scaffold protein domains at single synapses

Nanoscale reorganisation of synaptic proteins in Alzheimer's disease

Trans-synaptic molecular context of NMDA receptor nanodomains

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