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

Caroline C. Escoubas(University of California, San Francisco), Leah C. Dorman(University of California, San Francisco), Phi T. Nguyen(University of California, San Francisco), Christian Lagares-Linares(University of California, San Francisco), Haruna Nakajo(University of California, San Francisco), Sarah Anderson(University of California, San Francisco), Jerika J. Barron(University of California, San Francisco), Sarah D. Wade(University of California, San Francisco), Beatriz Cuevas(University of California, San Francisco), Ilia D. Vainchtein(University of California, San Francisco), Nicholas J. Silva(University of California, San Francisco), Ricardo Guajardo(University of California, San Francisco), Yinghong Xiao(University of California, San Francisco), Peter V. Lidsky(University of California, San Francisco), Ellen Wang(University of California, San Francisco), Brianna M. Rivera(University of California, San Francisco), Sunrae E. Taloma(University of California, San Francisco), Dong Kyu Kim(University of California, San Francisco), Elizaveta Kaminskaya(University of California, San Francisco), Hiromi Nakao-Inoue(University of California, San Francisco), Bjoern Schwer(University of California, San Francisco), Thomas D. Arnold(University of California, San Francisco), Ari B. Molofsky(University of California, San Francisco), Carlo Condello(University of California, San Francisco), Raul Andino(University of California, San Francisco), Tomasz J. Nowakowski(University of California, San Francisco), Anna V. Molofsky(University of California, San Francisco)
Cell
March 14, 2024
10.1016/j.cell.2024.02.020
Cited by 144Open Access
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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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