Type-I-interferon-responsive microglia shape cortical development and behavior
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Abstract
Microglia are brain-resident macrophages that shape neural circuit development and are implicated in neurodevelopmental diseases. Multiple microglial transcriptional states have been defined, but their functional significance is unclear. Here, we identify a type I interferon (IFN-I)-responsive microglial state in the developing somatosensory cortex (postnatal day 5) that is actively engulfing whole neurons. This population expands during cortical remodeling induced by partial whisker deprivation. Global or microglial-specific loss of the IFN-I receptor resulted in microglia with phagolysosomal dysfunction and an accumulation of neurons with nuclear DNA damage. IFN-I gain of function increased neuronal engulfment by microglia in both mouse and zebrafish and restricted the accumulation of DNA-damaged neurons. Finally, IFN-I deficiency resulted in excess cortical excitatory neurons and tactile hypersensitivity. These data define a role for neuron-engulfing microglia during a critical window of brain development and reveal homeostatic functions of a canonical antiviral signaling pathway in the brain.
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Interferon-responsive microglia have been shown to be highly phagocytic and actively shape cortical development.
“This is especially relevant given interferon-responsive microglia have been shown to be highly phagocytic and actively shape cortical development (76), suggesting that interferon-induced microglia pathologically and excessively prune synapses critical for physiological circuit maturation in the Ts21 dlPFC.”
From Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex (2026) · cites this paper as [76]
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- Authors
- Escoubas, C. C., Dorman, L. C., Nguyen, P. T., Lagares-Linares, C., Nakajo, H., Anderson, S. R., Barron, J. J., Wade, S. D., Cuevas, B., Vainchtein, I. D., Silva, N. J., Guajardo, R., Xiao, Y., Lidsky, P. V., Wang, E. Y., Rivera, B. M., Taloma, S. E., Kim, D. K., Kaminskaya, E., Nakao-Inoue, H., Schwer, B., Arnold, T. D., Molofsky, A. B., Condello, C., Andino, R., Nowakowski, T. J., & Molofsky, A. V.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Molofsky, Anna V.
- ORCID
- Escoubas, Caroline C.
- Dorman, Leah C.
- Nguyen, Phi T.
- Anderson, Sarah R.
- Barron, Jerika J.
- Wade, Sarah D.
- Vainchtein, Ilia D.
- Silva, Nicholas J.
- Guajardo, Ricardo
- Xiao, Yinghong
- Lidsky, Peter V.
- Wang, Ellen Y.
- Rivera, Brianna M.
- Taloma, Sunrae E.
- Kim, Dong Kyu
- Nakao-Inoue, Hiromi
- Schwer, Bjoern
- Arnold, Thomas D.
- Molofsky, Ari B.
- Condello, Carlo
- Andino, Raul
- Nowakowski, Tomasz J.
- Molofsky, Anna V.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2024-04
- Volume
- 187
- Issue
- 8
- Pages
- 1936-1954.e24
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC11015974
- OpenAlex
- W4392802477
- Cited by
- 179
- References
- 33
- Citations by year
- 2026: 77 · 2025: 61 · 2024: 32 · 2023: 4 · 2022: 5
- FWCI
- 24.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- Pew Charitable Trusts (R01MH119349, DP2MH116507)
- NIH (R01AG064363)
- UCSF
- NIMH (RF1MH121268, R01MH119349, DP2MH116507)
- NIA (RF1AG061874)
- National Science Foundation (1650113)
- University of California San Francisco Weill Institute for Neurosciences
- Sandler Foundation
- Burroughs Wellcome Fund
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- microglia, type I interferon, interferon receptor, DNA damage, somatosensory cortex, cortical development, whisker deprivation, cortical remodeling, excitatory neurons, tactile hypersensitivity, neurodevelopmental disorders, antiviral signaling, zebrafish
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