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Updated: Jun 14, 2026
Sex Differences in Mouse Hippocampal Astrocytes after In-Vitro Ischemia
Published on: October 25, 2016
Transient Impairment in Microglial Function Causes Sex-Specific Deficits in Synaptic and Hippocampal Function in Mice
Sahabuddin Ahmed1, Baruh Polis1, Sumit Jamwal1
1Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven CT, 06511, USA.
Abstract:
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.
Insights
Early life adversity impairs hippocampal development in male mice, affecting synaptic pruning and fear conditioning. Glial cell manipulation in mice reveals potential therapeutic targets for sex-specific effects.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Early life adversity is linked to hippocampal abnormalities, with males often more vulnerable.
- The hippocampus is crucial for learning and memory, undergoing significant development in early life.
- Microglia play a key role in synaptic pruning during development.
Approach:
- Used the limited bedding (LB) paradigm, a rodent model of early life adversity.
- Investigated microglial involvement in synaptic pruning and hippocampal function in adolescent mice.
- Examined the effects of microglial ablation and chemogenetic activation on synaptic and behavioral outcomes.
- Assessed astrocyte involvement in sex-specific effects of LB.
Key Points:
- LB exposure caused sex-specific deficits in male mice, including impaired fear conditioning and synaptic connectivity.
- LB impaired microglial-mediated synaptic pruning in young pups, with effects diminishing by adolescence.
- Transient microglial ablation mimicked LB-induced abnormalities, while activation reversed deficits in LB males.
- Astrocytes showed increased synaptic engulfment in LB females, suggesting a compensatory mechanism.
Conclusions:
- Glial cells, particularly microglia, are critical mediators of sex-specific hippocampal deficits following early life adversity.
- Targeting glial cell function presents a potential therapeutic strategy for conditions arising from early life stress.
- Astrocytic activity may contribute to the relative resilience observed in females exposed to early life adversity.
