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Synaptic pruning following NMDAR-dependent LTD preferentially affects isolated synapses

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Camus, Côme, Leval, Léa, Villicana-Munoz, Viviana, Jelinkova, Sarka, Compans, Benjamin, Gambino, Frédéric, Herzog, Etienne, Choquet, Daniel +1 more·2025·iScience
DOI 10.1016/j.isci.2025.113093PMC PMC12478112
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Abstract

Long-term depression (LTD) is an activity-dependent decrease in synaptic strength. This state initiates either a re-potentiation or a loss, aka pruning, of the synapse within hours to days following its induction. However, the precise relationship between LTD and synaptic pruning remains elusive. Using various imaging techniques and electrophysiology on neuronal cell culture, we reveal a direct relationship between LTD and synaptic pruning. All synapses that exhibit NMDAR-dependent LTD are pruned unless counteracted by input-specific activity. Additionally, we identify the post-synaptic ion channels pivotal for sensing pre-synaptic activity. Finally, we find that neighboring synapses displaying coordinated activity act as mutual safeguards against pruning. These distinctive properties mean that LTD-dependent synaptic pruning has a major impact on synapses that do not contribute to responses involved in network activity.

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  • LTD is associated with the loss of weak AZs, driving synapse shrinkage.

    “Conversely, LTD is associated with the loss of weak AZs, driving synapse shrinkage.”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [70]

    The Results section (‘NMDAR-dependent long-term depression triggers spine loss within 3 h’; page unavailable) reports that LTD was followed by loss of presynaptic Bassoon labeling and pruning of whole synapses. The Discussion (‘Postsynaptic density-95 reshuffling…’; page unavailable) describes complete loss of the spine, not shrinkage driven specifically by loss of weak active zones. The paper supports LTD-associated synapse loss, but not the claimed selection of weak AZs or that mechanism of shrinkage. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Microglia play a central role in activity-dependent synapse elimination by engulfing weak or unnecessary synapses.

    “Microglia, the brain’s resident immune cells, play a central role in activity-dependent synapse elimination by engulfing weak or unnecessary synapses [70,80].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [70]

    The Introduction describes activity-dependent synapse elimination, and the Discussion reports that synaptic activity and the activity of neighboring synapses influence which spines are lost. Neither those passages nor a search of our copy for microglia describes microglial engulfment or establishes that microglia play a central role in this process. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Neighboring synapses displaying coordinated activity act as mutual safeguards against pruning, ensuring that LTD-dependent elimination primarily impacts synapses that do not contribute to network activity responses.

    “However, neighboring synapses displaying coordinated activity act as mutual safeguards against pruning, ensuring that LTD-dependent elimination primarily impacts synapses that do not contribute to network activity responses [70].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [70]

  • Synaptic pruning is a neurodevelopmental process that refines neural circuitry by systematically eliminating excess or weak synaptic connections, shaping circuit connectivity and function.

    “Synaptic pruning is a neurodevelopmental process that refines neural circuitry by systematically eliminating excess or weak synaptic connections, shaping circuit connectivity and function [70].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [70]

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Cited by

Sorted by citations

Authors
Camus, C., Leval, L., Villicana-Munoz, V., Jelinkova, S., Compans, B., Gambino, F., Herzog, E., Choquet, D., & Hosy, E.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
Hosy, Eric
ORCID
Venue
iScience
Publisher
Elsevier BV
Published
2025-10
Volume
28
Issue
10
Pages
113093
ISSN
2589-0042 (ISSN-L)
DOI
10.1016/j.isci.2025.113093
PMC
PMC12478112
OpenAlex
W4413826749
Cited by
4
References
5
Citations by year
2026: 3 · 2025: 1
FWCI
1.57
Type
journal article
Language
en
Open access
Licence
Locations
  • iScience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Fondation pour la Recherche Médicale (HORIZON-MSCA-2021 EaSYFUN\u2013 10106258, ANR-20-COEN-0003-02)
  • European Commission Marie Sklodowska-Curie Actions
  • European Research Council (787340)
  • Centre National de la Recherche Scientifique
  • European Commission
  • European Research Executive Agency
  • Ministère de l'Enseignement supérieur et de la Recherche
  • Research Executive Agency
  • HORIZON EUROPE Health
  • French National Research Agency
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
synaptic pruning, long-term depression, network activity

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