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Cited by 548Neuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology ResearchNeurogenesis and neuroplasticity mechanisms

Microglia regulation of synaptic plasticity and learning and memory

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Zhou, Miou, Cornell, Jessica, Salinas, Shelbi, Huang, Hou-Yuan·2022·Neural Regeneration Research
DOI 10.4103/1673-5374.322423PMC PMC8530121
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Abstract

Microglia are the resident macrophages of the central nervous system. Microglia possess varied morphologies and functions. Under normal physiological conditions, microglia mainly exist in a resting state and constantly monitor their microenvironment and survey neuronal and synaptic activity. Through the C1q, C3 and CR3 "Eat Me" and CD47 and SIRPα "Don't Eat Me" complement pathways, as well as other pathways such as CX3CR1 signaling, resting microglia regulate synaptic pruning, a process crucial for the promotion of synapse formation and the regulation of neuronal activity and synaptic plasticity. By mediating synaptic pruning, resting microglia play an important role in the regulation of experience-dependent plasticity in the barrel cortex and visual cortex after whisker removal or monocular deprivation, and also in the regulation of learning and memory, including the modulation of memory strength, forgetfulness, and memory quality. As a response to brain injury, infection or neuroinflammation, microglia become activated and increase in number. Activated microglia change to an amoeboid shape, migrate to sites of inflammation and secrete proteins such as cytokines, chemokines and reactive oxygen species. These molecules released by microglia can lead to synaptic plasticity and learning and memory deficits associated with aging, Alzheimer's disease, traumatic brain injury, HIV-associated neurocognitive disorder, and other neurological or mental disorders such as autism, depression and post-traumatic stress disorder. With a focus mainly on recently published literature, here we reviewed the studies investigating the role of resting microglia in synaptic plasticity and learning and memory, as well as how activated microglia modulate disease-related plasticity and learning and memory deficits. By summarizing the function of microglia in these processes, we aim to provide an overview of microglia regulation of synaptic plasticity and learning and memory, and to discuss the possibility of microglia manipulation as a therapeutic to ameliorate cognitive deficits associated with aging, Alzheimer's disease, traumatic brain injury, HIV-associated neurocognitive disorder, and mental disorders.

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Crossref · 10.4103/1673-5374.322423

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  • Other eat me signals include phosphatidylserine exposure on dendrites, recognized by microglial TREM2, and CX3CR1/CX3CL1 signaling, which helps identify synapses for elimination.

    “Other “eat me” signals include phosphatidylserine (PS) exposure on dendrites, recognized by microglial TREM2, and CX3CR1/CX3CL1 signaling, which helps identify synapses for elimination [81,82,83].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [82]

  • C1q presynaptic tagging correlates with apoptotic markers, guiding pruning decisions.

    “C1q presynaptic tagging correlates with apoptotic markers, guiding pruning decisions [81,82,83].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [82]

  • Complement proteins, particularly C1q and C3, are produced by microglia or astrocytes and localize to apoptotic, immature, or weak developing synapses.

    “Complement proteins, particularly C1q (the initiating protein) and C3, are produced by microglia or astrocytes and localize to apoptotic, immature, or weak developing synapses.”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [82]

  • Tagged synapses are recognized and engulfed by microglial complement receptor 3 (CR3).

    “These tagged synapses are then recognized and engulfed by microglial complement receptor 3 (CR3).”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [82]

  • CD47 expressed by neurons binds to its receptor SIRPα on microglia, inhibiting phagocytosis of active synapses.

    “CD47, expressed by neurons, binds to its receptor SIRPα on microglia, inhibiting phagocytosis of active synapses [82].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [82]

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Authors
Zhou, M., Cornell, J., Salinas, S., & Huang, H.-Y.
Affiliations
Western University of Health Sciences (US)
Corresponding author
Zhou, Miou
ORCID
Venue
Neural Regeneration Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2022
Volume
17
Issue
4
Pages
705
ISSN
1673-5374 (ISSN-L)
DOI
10.4103/1673-5374.322423
PMC
PMC8530121
OpenAlex
W3196827409
Cited by
548
References
19
Citations by year
2026: 125 · 2025: 151 · 2024: 121 · 2023: 91 · 2022: 59
FWCI
8.18
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • Neural Regeneration Research (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
microglia, synaptic plasticity, learning and memory, synaptic pruning, complement pathway, microglial activation, neuroinflammation, Alzheimer's disease, traumatic brain injury, HIV-associated neurocognitive disorders, cognitive impairment

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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