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Background <p>Fragile X syndrome is caused by the loss of the <i>Fmr1</i> gene expression. Deletion of <i>Fmr1</i> 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 <i>Fmr1</i> expression in microglia leads to molecular and behavioral phenotypes.</p> Methods <p>We downregulated <i>Fmr1</i> in microglia during early and late postnatal development and studied the effect on microglial morphology and distinct behaviours.</p> Results <p>Female, but not male, adult mice with downregulation of <i>Fmr1</i> in microglia during early development exhibited reactive microglia and behavioral phenotypes, including enhanced self-grooming and alterations in social interaction. Downregulation of <i>Fmr1</i> in microglia during late development induced a milder phenotype, characterized by impaired preference for social novelty without affecting microglia morphology.</p> Conclusions <p>The downregulation of <i>Fmr1</i> and its encoded protein FMRP in microglia contributes to behavioural phenotypes in a sex-specific manner.</p>

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Postnatal downregulation of Fmr1 in microglia promotes microglial reactivity and causes behavioural alterations in female mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月7日

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  • Mehdi Hooshmandi,
  • David Ho-Tieng,
  • Kevin C. Lister,
  • Weihua Cai,
  • Calvin Wong,
  • Nicole Brown,
  • Jonathan Fan,
  • Volodya Hovhannisyan,
  • Sonali Uttam,
  • Masha Prager-Khoutorsky,
  • Nahum Sonenberg,
  • Christos G. Gkogkas,
  • Arkady Khoutorsky

摘要

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.