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Immunohistochemical Visualization of Hippocampal Neuron Activity After Spatial Learning in a Mouse Model of Neurodevelopmental Disorders
Published on: May 12, 2015
The microglial TREM2 receptor programs hippocampal development in a mouse model of childhood deprivation
Sahabuddin Ahmed1, Christian Bowers1, Jose Munoz-Martin2
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 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.
Insights
Childhood neglect impairs cognitive development by affecting microglia. Restoring Triggering Receptor Expressed on Myeloid cells 2 (TREM2) function through enrichment can reverse these negative effects on synaptic connectivity and learning.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Childhood neglect and deprivation are common adversities impacting cognitive development.
- Microglia-mediated synaptic pruning is crucial for cognitive development, and its disruption by early adversity is poorly understood.
- Previous studies linked limited bedding (LB) to impaired hippocampal function in male mice due to abnormal microglial pruning.
Purpose of the Study:
- To investigate the molecular mechanisms underlying microglial dysfunction in a mouse model of early life deprivation.
- To determine the role of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in mediating the effects of deprivation and enrichment on cognitive development.
Main Methods:
- Utilized a limited bedding (LB) mouse model to simulate early life deprivation.
- Assessed the expression of TREM2 in response to LB and manipulated TREM2 levels via overexpression.
- Evaluated microglial phagocytic function, synaptic connectivity, hippocampal function, and fear learning in response to LB and TREM2 manipulation.
- Investigated the impact of brief postnatal enrichment on LB mice.
Main Results:
- Limited bedding (LB) significantly reduced TREM2 expression in mice.
- TREM2 deficiency explained approximately half of the observed microglial phagocytic deficit in LB mice.
- Overexpression of TREM2 restored microglial phagocytic function and rescued deficits in hippocampal connectivity and fear learning.
- Postnatal enrichment normalized synaptic pruning in a TREM2-dependent manner and improved contextual fear conditioning in adolescent LB male mice.
Conclusions:
- TREM2 is a key molecular mediator of the long-term cognitive and synaptic consequences of early life deprivation.
- TREM2 activity during early development is critical for synaptic connectivity and cognitive function.
- Postnatal enrichment can mitigate the negative effects of deprivation on cognitive development through a TREM2-dependent pathway.
