Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity
Open accessAbstract
Synapse remodeling is essential to encode experiences into neuronal circuits. Here, we define a molecular interaction between neurons and microglia that drives experience-dependent synapse remodeling in the hippocampus. We find that the cytokine interleukin-33 (IL-33) is expressed by adult hippocampal neurons in an experience-dependent manner and defines a neuronal subset primed for synaptic plasticity. Loss of neuronal IL-33 or the microglial IL-33 receptor leads to impaired spine plasticity, reduced newborn neuron integration, and diminished precision of remote fear memories. Memory precision and neuronal IL-33 are decreased in aged mice, and IL-33 gain of function mitigates age-related decreases in spine plasticity. We find that neuronal IL-33 instructs microglial engulfment of the extracellular matrix (ECM) and that its loss leads to impaired ECM engulfment and a concomitant accumulation of ECM proteins in contact with synapses. These data define a cellular mechanism through which microglia regulate experience-dependent synapse remodeling and promote memory consolidation.
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The ECM can be modified rapidly by the release of proteases, by microglial action and by internalization, all of which can be activated by memory events.
“The ECM can be modified rapidly by the release of proteases [36], by microglial action and by internalization, all of which can be activated by memory events [37–39].”
From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [39]
The Results section, “Neuronal IL-33 Drives Microglial Engulfment of the ECM” (page unavailable), shows microglial internalization of an ECM protein, and the Discussion links IL-33 signaling to experience-dependent microglial activation and memory. The paper does not establish that a memory event rapidly triggers ECM internalization or remodeling. Protease release is separately cited to [36], so it is not assessed against this source. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMicroglia regulate axonal myelination, synaptic pruning, vasculature repair, and clearance of debris and toxic substances.
“These cells not only regulate axonal myelination, but also contribute to synaptic pruning, vasculature repair, and clearance of debris and toxic substances, among other important physiological roles [23–28].”
From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [24]
The Introduction (page unavailable) says microglia engulf synapse components, supporting their role in synaptic pruning. The Discussion, under “Microglia Remodel the Brain ECM” (page unavailable), asks whether microglia remodel myelin rather than establishing that they regulate myelination. The passages do not substantiate vasculature repair or clearance of debris and toxic substances. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMicroglia promote and assist various processes within the CNS, closely interacting with neurons, other glial cells, the neurovascular unit and the extracellular matrix.
“Microglia promote and assist with various processes within the CNS, closely interacting with neurons, other glial cells, the neurovascular unit and the extracellular matrix.”
From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [24]
The Introduction (page unavailable) describes microglial contact with neuronal spines and astrocyte-derived IL-33 driving microglial synapse engulfment. The Discussion (page unavailable) describes microglial remodeling of the extracellular matrix. These passages support several interactions in the claim, but our copy does not establish microglial interaction with the neurovascular unit. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIncreased contacts with pre- and post-synaptic elements in the WT group might indicate enhanced synapse plasticity and maintenance.
“Increased contacts with pre- and post-synaptic elements in the WT group might indicate enhanced synapse plasticity and maintenance, as microglia are known to constantly modulate synapses during normal physiological conditions [14, 24, 87].”
From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [24]
Microglial clearance of extracellular matrix in response to neuronal IL-33 promotes synaptic remodeling and plasticity in mice.
“Recent work in mice shows that microglial clearance of ECM in response to neuronal IL-33 promotes synaptic remodeling and plasticity [89].”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [89]
Inhibiting the IL-33 pathway enhances deposition of extracellular matrix at synapses.
“Importantly, inhibiting this pathway results in reduced microglial phagocytosis and engulfment of ECM components (e.g. aggrecan) and conversely enhanced deposition of ECM at synapses [89]”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [89]
Inhibiting the IL-33 pathway reduces microglial phagocytosis and engulfment of extracellular matrix components such as aggrecan.
“Importantly, inhibiting this pathway results in reduced microglial phagocytosis and engulfment of ECM components (e.g. aggrecan) and conversely enhanced deposition of ECM at synapses [89]”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [89]
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Function and therapeutic value of astrocytes in neurological diseases
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Myelin plasticity: sculpting circuits in learning and memory
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Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain
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Shaping Neuronal Fate: Functional Heterogeneity of Direct Microglia-Neuron Interactions
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The extracellular matrix and perineuronal nets in memory
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Directed evolution of adeno-associated virus for efficient gene delivery to microglia
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Human neuronal maturation comes of age: cellular mechanisms and species differences
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Microbiota‐microglia connections in age‐related cognition decline
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The VCAM1–ApoE pathway directs microglial chemotaxis and alleviates Alzheimer’s disease pathology
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Lysosomal Functions in Glia Associated with Neurodegeneration
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Cytokine Signalling at the Microglial Penta-Partite Synapse
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Microglia: Activity‐dependent regulators of neural circuits
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“In addition to regulation of synapse numbers in the developing brain, microglia have synaptogenic roles in the adult brain, based on work in the cortex, 17 hippocamus, 18 and olfactory bulb 19,20 (Figure 1A).”
BackgroundInfluentialBobotis, B. C., Khakpour, M., Braniff, O., de Andrade, E. G., Gargus, M., Allen, M., Carrier, M., Baillargeon, J., Rangachari, M., & Tremblay, M.-È. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03341-6 · Cited by 17 · see citing works
“Increased contacts with pre-and post-synaptic elements in the WT group might indicate enhanced synapse plasticity and maintenance, as microglia are known to constantly modulate synapses during normal physiological conditions [14, 24, 87].”
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Multifaceted response of microglia in the cuprizone model of demyelination
Shanahan, A., Eichfeld, G., Todd, L., & Niraula, A. (2026) · PLOS One · doi:10.1371/journal.pone.0355981
“This expansion was associated with a trend toward increased protein and mRNA expression of CD68, a lysosomal protein associated with phagocytosis and degradation of debris [30].”
- Authors
- Nguyen, P. T., Dorman, L. C., Pan, S., Vainchtein, I. D., Han, R. T., Nakao-Inoue, H., Taloma, S. E., Barron, J. J., Molofsky, A. B., Kheirbek, M. A., & Molofsky, A. V.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Molofsky, Anna V.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-07
- Volume
- 182
- Issue
- 2
- Pages
- 388-403.e15
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7497728
- OpenAlex
- W3039508055
- Cited by
- 615
- References
- 101
- Citations by year
- 2026: 70 · 2025: 124 · 2024: 101 · 2023: 99 · 2022: 108 · 2021: 88 · 2020: 23
- FWCI
- 31.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Science Foundation
- Esther A. and Joseph Klingenstein Fund
- Pew Charitable Trusts
- McKnight Foundation
- Burroughs Wellcome Fund
- National Institutes of Health
- 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, extracellular matrix, synaptic plasticity, IL-33, hippocampus, dendritic spine plasticity, fear memory, memory precision, aging, memory consolidation
- MeSH terms
- Interleukin-33, Interleukin-1 Receptor-Like 1 Protein, Aging, Animals, Extracellular Matrix, Fear, Gene Expression Regulation, Hippocampus, Memory, Mice, Inbred C57BL, Mice, Transgenic, Neuronal Plasticity, Neurons, Signal Transduction, Microglia, Mice
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