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Published on: May 12, 2015
Postnatal downregulation of Fmr1 in microglia promotes microglial reactivity and causes behavioural alterations in
Mehdi Hooshmandi1, David Ho-Tieng1, Kevin C Lister1
1Department of Anesthesia, Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC, Canada.
Background:
Fragile X syndrome is caused by the loss of the Fmr1 gene expression. Deletion of Fmr1 in various neuronal and non-neuronal subpopulations in the brain of mice leads to cell-type-specific effects. Microglia, immune cells critical for the refinement of neuronal circuits during brain development, have been implicated in various neurodevelopmental disorders, including fragile X syndrome. However, it is unknown whether reduced Fmr1 expression in microglia leads to molecular and behavioral phenotypes.
Methods:
We downregulated Fmr1 in microglia during early and late postnatal development and studied the effect on microglial morphology and distinct behaviours.
Results:
Female, but not male, adult mice with downregulation of Fmr1 in microglia during early development exhibited reactive microglia and behavioral phenotypes, including enhanced self-grooming and alterations in social interaction. Downregulation of Fmr1 in microglia during late development induced a milder phenotype, characterized by impaired preference for social novelty without affecting microglia morphology.
Conclusions:
The downregulation of Fmr1 and its encoded protein FMRP in microglia contributes to behavioural phenotypes in a sex-specific manner.
Insights
Reduced Fmr1 gene expression in microglia causes sex-specific behavioral changes in mice, impacting social interaction and grooming. This highlights microglia
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Fragile X syndrome stems from Fmr1 gene loss, affecting brain development.
- Microglia, crucial for neural circuit refinement, are implicated in neurodevelopmental disorders.
- The specific impact of Fmr1 reduction in microglia remains unclear.
Purpose of the Study:
- To investigate the consequences of reduced Fmr1 expression in microglia.
- To determine if Fmr1 downregulation in microglia elicits molecular and behavioral changes.
- To assess sex-specific effects of microglial Fmr1 reduction.
Main Methods:
- Downregulation of Fmr1 in mouse microglia during early and late postnatal development.
- Analysis of microglial morphology.
- Assessment of distinct behavioral phenotypes.
Main Results:
- Early Fmr1 downregulation in female microglia led to reactive microglia and behavioral changes (grooming, social interaction).
- Late Fmr1 downregulation caused milder phenotypes (impaired social novelty preference) without altering microglia morphology.
- Male mice did not exhibit these phenotypes.
Conclusions:
- Microglial Fmr1 downregulation contributes to behavioral phenotypes.
- These effects are sex-specific, with females showing more pronounced changes.
- FMRP, the protein encoded by Fmr1, plays a role in microglial function and behavior.
