Type-I-interferon-responsive microglia shape cortical development and behavior

Caroline C Escoubas; Leah C Dorman; Phi T Nguyen; Christian Lagares-Linares; Haruna Nakajo; Sarah R Anderson; Jerika J Barron; Sarah D Wade; Beatriz Cuevas; Ilia D Vainchtein; Nicholas J Silva; Ricardo Guajardo; Yinghong Xiao; Peter V Lidsky; Ellen Y Wang; Brianna M Rivera; Sunrae E Taloma; Dong Kyu Kim; Elizaveta Kaminskaya; Hiromi Nakao-Inoue; Bjoern Schwer; Thomas D Arnold; Ari B Molofsky; Carlo Condello; Raul Andino; Tomasz J Nowakowski; Anna V Molofsky

doi:10.1016/j.cell.2024.02.020

Type-I-interferon-responsive microglia shape cortical development and behavior

Cell. 2024 Apr 11;187(8):1936-1954.e24. doi: 10.1016/j.cell.2024.02.020. Epub 2024 Mar 14.

Authors

Caroline C Escoubas¹, Leah C Dorman², Phi T Nguyen³, Christian Lagares-Linares¹, Haruna Nakajo¹, Sarah R Anderson¹, Jerika J Barron³, Sarah D Wade², Beatriz Cuevas², Ilia D Vainchtein¹, Nicholas J Silva¹, Ricardo Guajardo⁴, Yinghong Xiao⁵, Peter V Lidsky⁵, Ellen Y Wang⁶, Brianna M Rivera⁷, Sunrae E Taloma², Dong Kyu Kim¹, Elizaveta Kaminskaya¹, Hiromi Nakao-Inoue¹, Bjoern Schwer⁸, Thomas D Arnold⁹, Ari B Molofsky¹⁰, Carlo Condello¹¹, Raul Andino⁵, Tomasz J Nowakowski¹², Anna V Molofsky¹³

Affiliations

¹ Departments of Psychiatry and Behavioral Sciences/Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
² Departments of Psychiatry and Behavioral Sciences/Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
³ Departments of Psychiatry and Behavioral Sciences/Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
⁴ Departments of Psychiatry and Behavioral Sciences/Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA; Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94158, USA.
⁵ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
⁶ Departments of Psychiatry and Behavioral Sciences/Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; UCSF SRTP program, University of California, San Francisco, San Francisco, CA 94158, USA.
⁷ Institute for Neurodegenerative Diseases/Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
⁸ Departments of Psychiatry and Behavioral Sciences/Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Bakar Aging Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
⁹ Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA.
¹⁰ Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
¹¹ Institute for Neurodegenerative Diseases/Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
¹² Departments of Psychiatry and Behavioral Sciences/Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158, USA; Chan-Zuckerberg Biohub, San Francisco, CA 94158, USA.
¹³ Departments of Psychiatry and Behavioral Sciences/Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: anna.molofsky@ucsf.edu.

PMID: 38490196
PMCID: PMC11015974 (available on 2025-04-11)
DOI: 10.1016/j.cell.2024.02.020

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.

Keywords: cortical development; microglia; neuroimmunity; phagocytosis; somatosensory cortex; tactile hypersensitivity; type I interferon.

MeSH terms

Animals
Brain* / cytology
Brain* / growth & development
Interferon Type I* / metabolism
Mice
Microglia* / metabolism
Neurons / metabolism
Zebrafish

Substances

Interferon Type I

Abstract

MeSH terms

Substances

Grants and funding