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The Microglial TREM2 Receptor Programs Hippocampal Development in a Mouse Model of Childhood Deprivation
Sahabuddin Ahmed1, Christian Bowers1, Jose Munoz-Martin1,2,3
1Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven CT, 06511, USA.
Abstract:
Childhood neglect and deprivation are the most common forms of adversity, yet their biological impact on cognitive development-and how enrichment mitigates these effects-remains unclear. Using limited bedding (LB) as a mouse model of deprivation, we previously showed that abnormal microglial-mediated synaptic pruning during the second and third postnatal weeks leads to impaired synaptic connectivity and hippocampal dysfunction, particularly in males. Here, we demonstrate that LB reduces expression of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in different mouse strains and that TREM2 deficiency contributes to, but does not fully explain, impaired microglial pruning. Overexpressing TREM2 restored microglial phagocytic function and rescued deficits in hippocampal connectivity and fear learning. Brief postnatal enrichment (P14-P17) also normalized synaptic pruning in a TREM2-dependent manner. Together, our findings identify TREM2 as a key molecular mediator of experience-dependent plasticity, revealing its central role in linking early-life deprivation and enrichment to cognitive outcomes later in life.
Insights
Childhood neglect impacts brain development via altered microglial pruning. Restoring Triggering Receptor Expressed on Myeloid cells 2 (TREM2) function or providing early enrichment can rescue these cognitive deficits.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Childhood neglect is a common adversity impacting cognitive development.
- Microglial-mediated synaptic pruning is crucial during early development.
- The role of TREM2 in mediating effects of early-life adversity on cognition is not fully understood.
Purpose of the Study:
- To investigate the biological impact of early-life deprivation on cognitive development.
- To explore the role of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in microglial function and synaptic pruning.
- To determine if postnatal enrichment can mitigate deprivation-induced cognitive deficits.
Main Methods:
- Utilized a limited bedding (LB) mouse model for deprivation.
- Assessed microglial function, synaptic pruning, and hippocampal connectivity.
- Manipulated TREM2 expression and evaluated effects of postnatal enrichment.
Main Results:
- Limited bedding (LB) reduced TREM2 expression and impaired microglial pruning.
- TREM2 deficiency partially explained, but did not fully account for, pruning deficits.
- Overexpressing TREM2 restored microglial phagocytosis and rescued cognitive impairments.
- Postnatal enrichment normalized synaptic pruning in a TREM2-dependent manner.
Conclusions:
- TREM2 is a critical molecular mediator of experience-dependent plasticity.
- TREM2 links early-life deprivation and enrichment to long-term cognitive outcomes.
- Targeting TREM2 may offer therapeutic potential for cognitive deficits resulting from early adversity.
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