Jamwal, S. | Search bioRxiv

bioRxiv2025

The Microglial TREM2 Receptor Programs Hippocampal Development in a Mouse Model of Childhood Deprivation

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.

neuroscience↗

bioRxiv2024

Postnatal Enrichment Corrects Deficits in Perineuronal Net Formation and Reversal Learning in Adult Mice Exposed to Early Adversity

Withdrawal StatementThe authors have withdrawn this manuscript because the behavioral studies using the Barnes maze were not conducted according to the methods described, specifically regarding the animals ability to locate the escape hole independently. Furthermore, the authors were unable to replicate the behavioral outcomes originally reported when the experiments were repeated following the stated methods. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

neuroscience↗

bioRxiv2024

Transient Impairment in Microglial Function Causes Sex-Specific Deficits in Synaptic and Hippocampal Function in Mice Exposed to Early Adversity

Abnormal development and function of the hippocampus are two of the most consistent findings in humans and rodents exposed to early life adversity, with males often being more affected than females. Using the limited bedding (LB) paradigm as a rodent model of early life adversity, we found that male adolescent mice that had been exposed to LB exhibit significant deficits in contextual fear conditioning and synaptic connectivity in the hippocampus, which are not observed in females. This is linked to altered developmental refinement of connectivity, with LB severely impairing microglial-mediated synaptic pruning in the hippocampus of male and female pups on postnatal day 17 (P17), but not in adolescent P33 mice when levels of synaptic engulfment by microglia are substantially lower. Since the hippocampus undergoes intense synaptic pruning during the second and third weeks of life, we investigated whether microglia are required for the synaptic and behavioral aberrations observed in adolescent LB mice. Indeed, transient ablation of microglia from P13-21, in normally developing mice caused sex-specific behavioral and synaptic abnormalities similar to those observed in adolescent LB mice. Furthermore, chemogenetic activation of microglia during the same period reversed the microglial-mediated phagocytic deficits at P17 and restored normal contextual fear conditioning and synaptic connectivity in adolescent LB male mice. Our data support an additional contribution of astrocytes in the sex-specific effects of LB, with increased expression of the membrane receptor MEGF10 and enhanced synaptic engulfment in hippocampal astrocytes of 17-day-old LB females, but not in LB male littermates. This finding suggests a potential compensatory mechanism that may explain the relative resilience of LB females. Collectively, these studies highlight a novel role for glial cells in mediating sex-specific hippocampal deficits in a mouse model of early-life adversity.

neuroscience↗