Abstract

BackgroundThe postnatal maturation of microglia is essential for neural circuit refinement, yet its molecular regulators remain incompletely defined. TREM2, a key Alzheimer's disease risk gene, is implicated in microglial function, but its role in developmental timing is unclear.ObjectiveTo determine whether TREM2 regulates the postnatal maturation of microglia and to assess the cellular, molecular, and behavioral consequences of TREM2 deficiency.MethodsWe performed longitudinal transcriptomic profiling of Trem2-knockout and control microglia. Morphological analyses were conducted alongside evaluation of synaptic pruning from postnatal day 7, 14, and 21. Adult mice were behaviorally tested at baseline and after immune challenge.ResultsTrem2-knockout disrupted stage-specific transcriptional programs, decoupled PRC2 subunit expression, and impaired repression of early developmental genes. This dysregulation coincided with persistent mitochondrial and metabolic deficits. Trem2-knockout microglia exhibited simplified morphology, reduced density, and impaired synaptic pruning, leading to excessive synaptic retention. In adulthood, these mice displayed heightened anxiety-like and repetitive behaviors, which worsened after immune challenge.ConclusionsOur study identifies TREM2 as a regulator of microglial developmental timing and links aberrant postnatal microglial maturation to lifelong behavioral vulnerabilities, providing mechanistic insight into neurodevelopmental risk.