The microglial TREM2 receptor programs hippocampal development in a mouse model of childhood deprivation.

Childhood neglect and deprivation are the most common forms of early adversity, yet their biological impact on cognitive development-and how enrichment mitigates these effects-remains poorly understood. Using limited bedding (LB) as a mouse model of deprivation, we previously showed that abnormal microglia-mediated synaptic pruning during the second and third postnatal weeks impairs synaptic connectivity and hippocampal function, particularly in males. However, the molecular basis of this microglial dysfunction is unclear. Here, we demonstrate that LB reduces expression of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) across multiple mouse strains and that TREM2 deficiency accounts for roughly half of the phagocytic deficit. Overexpressing TREM2 restores microglial phagocytic function and rescues deficits in hippocampal connectivity and fear learning later in life. Brief postnatal enrichment normalizes synaptic pruning in a TREM2-dependent manner and restores contextual fear conditioning in adolescent LB male mice. Together, these findings identify TREM2 activity during early development as a key mediator of the long-term impact of deprivation and enrichment on synaptic connectivity and cognitive function.