Forged Without FIRE: Normal Brain Development in the Absence of Microglia

Typical development of synaptic and neuronal properties can proceed without microglia in the cortex and thalamus O'Keeffe M, Booker SA, Walsh D, Li M, Henley C, Simões de Oliveira L, Liu M, Wang X, Banqueri M, Ridley K, Dissanayake KN, Martinez-Gonzalez C, Craigie KJ, Vasoya D, Leah T, He X, Hume DA, Duguid I, Nolan MF, Qiu J, Wyllie DJA, Dando OR, Gonzalez-Sulser A, Gan J, Pridans C, Kind PC, Hardingham GE. Nat Neurosci . 2025 Feb;28(2):268-279. doi: 10.1038/s41593-024-01833-x . Epub 2025 Jan 6. PMID: 39762658; PMCID: PMC11802452. Brain-resident macrophages, microglia, have been proposed to have an active role in synaptic refinement and maturation, influencing plasticity and circuit-level connectivity. Here we show that several neurodevelopmental processes previously attributed to microglia can proceed without them. Using a genetically modified mouse that lacks microglia (Csf1r ΔFIRE/ΔFIRE ), we find that intrinsic properties, synapse number and synaptic maturation are largely normal in the hippocampal CA1 region and somatosensory cortex at stages where microglia have been implicated. Seizure susceptibility and hippocampal-prefrontal cortex coherence in awake behaving animals, processes that are disrupted in mice deficient in microglia-enriched genes, are also normal. Similarly, eye-specific segregation of inputs into the lateral geniculate nucleus proceeds normally in the absence of microglia. Single-cell and single-nucleus transcriptomic analyses of neurons and astrocytes did not uncover any substantial perturbation caused by microglial absence. Thus, the brain possesses remarkable adaptability to execute developmental synaptic refinement, maturation and connectivity in the absence of microglia.