biostudies-literatureO'Brien CANational Institute of Neurological Disorders and StrokeChildren's Hospital of PhiladelphiaSilicon Valley Community FoundationNINDS NIH HHSNational Institute of Dental and Craniofacial ResearchNational Institutes of HealthNIH HHS6248-6264https://www.ebi.ac.uk/biostudies/studies/S-EPMC12444772biostudies-literatureUnknown33(12)Microglia replacement therapy, where endogenous brain macrophages are depleted and replaced by adoptively transferred surrogates, holds promise for treating pediatric neurologic diseases, but little is known about how early-life microglia replacement impacts the brain. We sought to investigate how early postnatal microglia depletion and adoptive macrophage transfer, essential components of microglia replacement, durably impact neural circuits in a mouse model. Using both pharmacologic and genetic models, postnatal microglia depletion worsened adult seizure severity, mortality, and neuropathology in a chemical seizure model. Replacement of endogenous microglia by adoptive transfer of monocytes rescued this effect, while transfer of authentic microglia from a donor mouse did not, and even woMolecular therapy : the journal of the American Society of Gene TherapyNeonatal microglia replacement in mice modulates seizure severity in adulthood.PMC12444772R21 NS135366DP5 OD036159DP5OD036159R21 NS128745T32 NS007413R01 NS1200992023-33184R01 NS129737R01 NS120960R01-NS-120960R01-NS-129737-01Cohen ASBennett MLBennett FCShukla SLevitt EMDelcy SASO'Brien CAfalseNeonatal microglia replacement in mice modulates seizure severity in adulthood.Microglia replacement therapy, where endogenous brain macrophages are depleted and replaced by adoptively transferred surrogates, holds promise for treating pediatric neurologic diseases, but little is known about how early-life microglia replacement impacts the brain. We sought to investigate how early postnatal microglia depletion and adoptive macrophage transfer, essential components of microglia replacement, durably impact neural circuits in a mouse model. Using both pharmacologic and genetic models, postnatal microglia depletion worsened adult seizure severity, mortality, and neuropathology in a chemical seizure model. Replacement of endogenous microglia by adoptive transfer of monocytes rescued this effect, while transfer of authentic microglia from a donor mouse did not, and even wo2025-01-01T00:00:00Z2025 Dec2026-07-15T07:45:38.084Z2026-07-01T03:08:03.588ZS-EPMC124447724087303310.1016/j.ymthe.2025.08.039