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Cited by 22Neuroscience and Neuropharmacology ResearchMemory and Neural MechanismsNeural dynamics and brain function

Synapse-specific structural plasticity that protects and refines local circuits during LTP and LTD

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Harris, Kristen M., Kuwajima, Masaaki, Flores, Juan C., Zito, Karen·2024·Philosophical Transactions of the Royal Society B: Biological Sciences
DOI 10.1098/rstb.2023.0224PMC PMC11529630
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Abstract

Synapses form trillions of connections in the brain. Long-term potentiation (LTP) and long-term depression (LTD) are cellular mechanisms vital for learning that modify the strength and structure of synapses. Three-dimensional reconstruction from serial section electron microscopy reveals three distinct pre- to post-synaptic arrangements: strong active zones (AZs) with tightly docked vesicles, weak AZs with loose or non-docked vesicles, and nascent zones (NZs) with a postsynaptic density but no presynaptic vesicles. Importantly, LTP can be temporarily saturated preventing further increases in synaptic strength. At the onset of LTP, vesicles are recruited to NZs, converting them to AZs. During recovery of LTP from saturation (1-4 h), new NZs form, especially on spines where AZs are most enlarged by LTP. Sentinel spines contain smooth endoplasmic reticulum (SER), have the largest synapses and form clusters with smaller spines lacking SER after LTP recovers. We propose a model whereby NZ plasticity provides synapse-specific AZ expansion during LTP and loss of weak AZs that drive synapse shrinkage during LTD. Spine clusters become functionally engaged during LTP or disassembled during LTD. Saturation of LTP or LTD probably acts to protect recently formed memories from ongoing plasticity and may account for the advantage of spaced over massed learning. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

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  • During a single LTP event, heterogeneity is resolved through rapid structural remodeling where 'nascent zones' are converted into functional active zones within 5 min via recruitment of dense-core vesicles.

    “During a single LTP event, this heterogeneity is resolved through rapid structural remodeling where ‘nascent zones’ are converted into functional active zones within 5 min via the recruitment of dense-core vesicles, representing a high turnover rate of these nanoblocks to saturate potentiation capacity [36,37].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [37]

    Section 4 reports that dense-core vesicles are recruited by 5 min after LTP induction and can fill a nascent zone, converting it to an active zone. It does not establish that conversion is complete within 5 min: nascent-zone frequency was unchanged at that point and diminished by 30 min. Section 9 describes conversion as occurring 'within minutes' but gives no five-minute deadline. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • These DCVs dock and convert NZs into functional active zones (AZs) in less than 5 min, a process that saturates potentiation capacity until new NZs are generated.

    “These DCVs dock and convert NZs into functional active zones (AZs) in less than 5 min, a process that saturates potentiation capacity until new NZs are generated [37].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [37]

    Section 4 says DCVs are recruited to boutons by 5 minutes after LTP induction and that a DCV with its tethered vesicles can fill a nascent zone and convert it to an active zone. It also suggests that filling nascent zones saturates LTP until the zones regrow. It does not establish that conversion occurs in less than 5 minutes; section 7 places the proposed sequence of conversion events within the first 30 minutes. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • During recovery, new NZs form on spines where AZs were most enlarged; these sentinel spines are often associated with the presence of smooth endoplasmic reticulum (SER) and form clusters with smaller spines.

    “During recovery, new NZs form on spines where AZs were most enlarged; these ‘sentinel spines’ are often associated with the presence of smooth endoplasmic reticulum (SER) and form clusters with smaller spines [37].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [37]

  • Three-dimensional reconstructions from electron microscopy reveal that during LTP induction, dense-core vesicles (DCVs) that carry tethered presynaptic vesicles are recruited to silent nascent zones (NZs).

    “Three-dimensional reconstructions from electron microscopy reveal that during LTP induction, dense-core vesicles (DCVs) that carry tethered presynaptic vesicles are recruited to silent nascent zones (NZs).”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [37]

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Sorted by citations

  • 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

    “During recovery, new NZs form on spines where AZs were most enlarged; these ‘sentinel spines’ are often associated with the presence of smooth endoplasmic reticulum (SER) and form clusters with smaller spines [37].”

Authors
Harris, K. M., Kuwajima, M., Flores, J. C., & Zito, K.
Affiliations
  • The University of Texas at Austin (US)
  • University of California, Davis (US)
Corresponding author
Harris, Kristen M.
ORCID
Venue
Philosophical Transactions of the Royal Society B: Biological Sciences
Publisher
The Royal Society
Published
2024-06-10
Volume
379
Issue
1906
Pages
20230224-20230224
ISSN
  • 0962-8436 (ISSN-L)
  • 1471-2970
DOI
10.1098/rstb.2023.0224
PMC
PMC11529630
OpenAlex
W4399500642
Cited by
22
References
17
Citations by year
2026: 13 · 2025: 8 · 2024: 1
FWCI
3.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Philosophical Transactions of the Royal Society B Biological Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute of Mental Health
  • Division of Biological Infrastructure
  • National Institute of Neurological Disorders & Stroke (R01NS06736)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
Keywords
long-term potentiation, long-term depression, synaptic plasticity, active zone, synaptic vesicle docking, dendritic spines, smooth endoplasmic reticulum, memory consolidation, serial section electron microscopy
MeSH terms
Animals, Models, Neurological, Neuronal Plasticity, Synapses, Long-Term Potentiation, Long-Term Synaptic Depression, Dendritic Spines

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