Microglial TREM2 Mediates Hippocampal Synaptic and Cognitive Sequela of Early Deprivation and Enrichment

PROJECT SUMMARY/ABSTRACT Childhood neglect accounts for 60% of all early life adversities and is associated with profound cortical thinning, hyperactivity, and cognitive deficits that include impaired hippocampal dependent memory. The molecular and cellular mechanisms responsible for these neurodevelopmental changes are difficult to study in humans and no animal models have yet replicated key structural and behavioral features of early deprivation/neglect. Here we show that mice pups raised under impoverished conditions of limited bedding and no nesting material (LB) show behavioral and structural changes that resemble those seen in children exposed to early neglect and that enrichment during the 2nd-3rd week of life corrects the hippocampal-dependent deficits seen in LB mice. In this proposal we hypothesize that LB inhibits the expression of the TREM2 receptor on microglia during peak synaptic pruning in the hippocampus. Abnormal synaptic pruning during the 2nd-3rd weeks of life leads to the retention of immature/non-functional spines resulting in immature and inefficient hippocampal circuitry characterized by low synaptic maturity index, reduced local functional connectivity in resting state fMRI, lower density of glutamatergic synapses, and impaired hippocampal function. Work in aim 1 will test whether overexpression of TREM2 is sufficient to correct the synaptic and cognitive abnormalities seen in adolescent LB mice. Chemogenetic activation of microglia and exposure to enrichment both increase levels of TREM2 and normalize microglial phagocytic activity. Studies proposed in aim 2 will test whether localized chemogenetic activation of microglia in the dorsal hippocampus from P13-17 can reverse the synaptic and cognitive deficits seen in LB adolescent mice. In aim 3 we will use Trem2 knockout mice to test whether the improved hippocampal function seen with enrichment, requires Trem2. Successful completion of this proposal will be the first to demonstrate that early neglect impairs synaptic pruning by reducing the expression of Trem2 and that these developmental abnormalities can be reversed with enrichment. These findings will provide a conceptually novel model to explain how deprivation and enrichment impact cognitive development and will hopefully inspire future collaborations to examine the effects of early neglect/enrichment on rsfMRI local functional connectivity in children.