Microglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling

Affiliations

¹ Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. Electronic address: travis.faust@umassmed.edu.
² Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
³ Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
⁴ Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
⁵ Nash Family Department of Neuroscience, Friedman Brain Institute, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, the Rockefeller University, New York, NY 10065, USA.
⁶ Department of Cell Biology, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
⁷ Department of Cell Biology, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
⁸ Nash Family Department of Neuroscience, Friedman Brain Institute, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Neuroscience Initiative, Advanced Science Research Center, Graduate Program in Biology, Graduate Program in Biochemistry, The City University of New York Graduate Center, New York, NY 10031, USA.
⁹ Nash Family Department of Neuroscience, Friedman Brain Institute, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Max Planck Institute for Biology of Ageing, CECAD, Cologne University, 50931 Cologne, Germany.
¹⁰ Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. Electronic address: dorothy.schafer@umassmed.edu.

PMID: 40934914
PMCID: PMC12489809 (available on 2026-09-10)
DOI: 10.1016/j.cell.2025.08.023

Microglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling

Travis E Faust et al. Cell. 2025.

. 2025 Sep 18;188(19):5212-5230.e21.

doi: 10.1016/j.cell.2025.08.023. Epub 2025 Sep 10.

Authors

Affiliations

¹ Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. Electronic address: travis.faust@umassmed.edu.
² Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
³ Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
⁴ Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
⁵ Nash Family Department of Neuroscience, Friedman Brain Institute, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, the Rockefeller University, New York, NY 10065, USA.
⁶ Department of Cell Biology, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
⁷ Department of Cell Biology, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
⁸ Nash Family Department of Neuroscience, Friedman Brain Institute, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Neuroscience Initiative, Advanced Science Research Center, Graduate Program in Biology, Graduate Program in Biochemistry, The City University of New York Graduate Center, New York, NY 10031, USA.
⁹ Nash Family Department of Neuroscience, Friedman Brain Institute, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Max Planck Institute for Biology of Ageing, CECAD, Cologne University, 50931 Cologne, Germany.
¹⁰ Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. Electronic address: dorothy.schafer@umassmed.edu.

PMID: 40934914
PMCID: PMC12489809 (available on 2026-09-10)
DOI: 10.1016/j.cell.2025.08.023

Abstract

Astrocytes and microglia are emerging key regulators of activity-dependent synapse remodeling that engulf and remove synapses in response to changes in neural activity. Yet, the degree to which these cells communicate to coordinate this process remains an open question. Here, we use whisker removal in postnatal mice to induce activity-dependent synapse removal in the barrel cortex. We show that astrocytes do not engulf synapses in this paradigm. Instead, astrocytes reduce contact with synapses prior to microglia-mediated synapse engulfment. We further show that the reduced astrocyte-synapse contact is dependent on the release of Wnts from microglia downstream of neuron-to-microglia fractalkine ligand-receptor (CX3CL1-CX3CR1) signaling. These results demonstrate an activity-dependent mechanism by which microglia instruct astrocyte-synapse interactions, providing a permissive environment for microglia to remove synapses. We further show that this mechanism is critical to remodel synapses in a changing sensory environment and that this signaling is upregulated in several disease contexts.

Keywords: Wnt; astrocyte; microglia; synapse remodeling.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Update of

Microglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling.
Faust TE, Lee YH, O'Connor CD, Boyle MA, Gunner G, Badimon A, Ayata P, Schaefer A, Schafer DP. Faust TE, et al. bioRxiv [Preprint]. 2024 Feb 9:2024.02.08.579178. doi: 10.1101/2024.02.08.579178. bioRxiv. 2024. Update in: Cell. 2025 Sep 18;188(19):5212-5230.e21. doi: 10.1016/j.cell.2025.08.023. PMID: 38370645 Free PMC article. Updated. Preprint.

References

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Microglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling

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Microglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling

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