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

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $715,999

## Abstract

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.

## Key facts

- **NIH application ID:** 11049675
- **Project number:** 1R01MH136490-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** ARIE KAFFMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $715,999
- **Award type:** 1
- **Project period:** 2024-09-18 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11049675

## Citation

> US National Institutes of Health, RePORTER application 11049675, Microglial TREM2 Mediates Hippocampal Synaptic and Cognitive Sequela of Early Deprivation and Enrichment (1R01MH136490-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11049675. Licensed CC0.

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