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Cited by 16Neuroscience and Neuropharmacology ResearchReceptor Mechanisms and SignalingGenetics and Neurodevelopmental Disorders

Trans-synaptic molecular context of NMDA receptor nanodomains

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Anderson, Michael C., Dharmasri, Poorna A., Damenti, Martina, Metzbower, Sarah R., Laghaei, Rozita, Blanpied, Thomas A., Levy, Aaron D.·2025·Nature Communications
DOI 10.1038/s41467-025-62766-yPMC PMC12343948

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Abstract

Tight coordination of spatial relationships between protein complexes is required for cellular function. In neuronal synapses, proteins responsible for neurotransmission form 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 key NMDAR subunits relative to active zone and post-synaptic density reference proteins using multiplexed super-resolution DNA-PAINT microscopy in rat hippocampal neurons. GluN2A and GluN2B subunits formed diverse nanoclusters that, surprisingly, were not localized near presynaptic vesicle release sites marked by Munc13-1. However, a subset of release sites was enriched with NMDARs, and modeling indicated this nanotopography promotes NMDAR activation. These enriched sites were internally denser with Munc13-1, aligned with PSD-95, and closely associated with specific NMDAR nanodomains. NMDAR activation rapidly reorganized this relationship, suggesting a structural mechanism for tuning NMDAR-mediated synaptic transmission. These findings suggest synaptic functional architecture depends on assembly of and trans-cellular spatial relationships between multiprotein nanodomains.

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  • PSD-95 assumes the synaptic trafficking function during synapse maturation, including the replacement of NR2B-NMDARs with NR2A-NMDARs.

    “Notably, SAP102 mediates the synaptic trafficking of both AMPA and NMDA receptors during early synaptogenesis [49], while PSD-95 assumes this function during synapse maturation, including the crucial replacement of NR2B-NMDARs with NR2A-NMDARs [40,50].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [50]

    The Discussion (page unavailable) reports that GluN2A may bind PSD-95 preferentially over GluN2B and discusses NMDAR composition in mature synapses. It does not say that PSD-95 takes over synaptic receptor trafficking during maturation or causes NR2B-containing NMDARs to be replaced by NR2A-containing NMDARs. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Only a subset of release sites aligned with PSD-95 forms enriched nanocolumns containing GluN2A/B, where NMDAR activation rapidly reorganizes this topography to tune synaptic transmission.

    “Only a subset of release sites aligned with PSD-95 forms enriched ‘nanocolumns’ containing GluN2A/B, where NMDAR activation rapidly reorganizes this topography to tune synaptic transmission [50].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [50]

    The Introduction and Discussion report that only a subset of release sites align with PSD-95-rich nanocolumns enriched in GluN2A/B, and the Results report rapid reorganization after NMDAR activation. The Discussion describes tuning of NMDAR-mediated synaptic transmission as a suggested mechanism, not a demonstrated effect of that reorganization. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Spatial segregation allows independent release sites to activate unique ratios of NMDAR subunits, expanding the computational capacity of single synapses.

    “This spatial segregation allows independent release sites to activate unique ratios of NMDAR subunits, expanding the computational capacity of single synapses [50].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [50]

    The Discussion (page not provided) proposes that spatial segregation may let vesicles released at different sites activate unique ratios of GluN2A- and GluN2B-containing receptors, expanding a synapse’s computational potential. The citing sentence presents this proposed effect as established, whereas the source says it 'raises the possibility' and is 'likely.' (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Super-resolution mapping using DNA-PAINT has revealed that NMDARs are typically absent from the region immediately opposing Munc13-1 release sites.

    “However, super-resolution mapping using DNA-PAINT has revealed that NMDARs are typically absent from the region immediately opposing Munc13-1 release sites.”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [50]

  • Sorting Nexin 27 (SNX27) is implicated in regulating NMDAR recycling from endosomes back to the plasma membrane.

    “Sorting Nexin 27 (SNX27) is also implicated in regulating NMDAR recycling from endosomes back to the plasma membrane [48,50].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [50]

    The Results section describes surface labeling and localization of NMDAR subunits, but does not address SNX27-mediated recycling. Searches for SNX27 and for endosomal recycling to the plasma membrane found no passage supporting the attributed claim in our copy. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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  • Molecular Physiology of the Neuronal Synapse

    Ramírez-Expósito, M. J., Cueto-Ureña, C., & Martínez-Martos, J. M. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48010088 · Cited by 6 · see citing works

    “Notably, SAP102 mediates the synaptic trafficking of both AMPA and NMDA receptors during early synaptogenesis [49], while PSD-95 assumes this function during synapse maturation, including the crucial replacement of NR2B-NMDARs with NR2A-NMDARs [40,50].”
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Authors
Anderson, M. C., Dharmasri, P. A., Damenti, M., Metzbower, S. R., Laghaei, R., Blanpied, T. A., & Levy, A. D.
Affiliations
  • University of Maryland, Baltimore (US)
  • Nikon (United States) (US)
  • Pittsburgh Supercomputing Center (US)
Corresponding author
  • Blanpied, Thomas A.
  • Levy, Aaron D.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-08-12
Volume
16
Issue
1
Pages
7460-7460
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-025-62766-y
PMC
PMC12343948
OpenAlex
W4413102840
Cited by
16
References
9
Citations by year
2026: 10 · 2025: 4 · 2024: 2
FWCI
5.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R37MH080046, R01MH11982, F331MH124283, F32MH119687, F31MH117920)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
NMDA receptor, nanoclusters, GluN2A, GluN2B, Munc13-1, PSD-95, active zone, postsynaptic density, presynaptic release sites, synaptic transmission, hippocampal neurons, DNA-PAINT, receptor activation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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