Astrocytic Contributions to Synaptic and Learning Abnormalities in a Mouse Model of Fragile X Syndrome

Jennifer L. Hodges, Xinzhu Yu, Anthony Gilmore, Hannah Bennett, Michelle Tjia, James F. Perna, Chia Chien Chen, Xiang Li, Ju Lu, Yi Zuo

Research output: Contribution to journalArticlepeer-review

Abstract

Background Fragile X syndrome (FXS) is the most common type of mental retardation attributable to a single-gene mutation. It is caused by FMR1 gene silencing and the consequent loss of its protein product, fragile X mental retardation protein. Fmr1 global knockout (KO) mice recapitulate many behavioral and synaptic phenotypes associated with FXS. Abundant evidence suggests that astrocytes are important contributors to neurological diseases. This study investigates astrocytic contributions to the progression of synaptic abnormalities and learning impairments associated with FXS. Methods Taking advantage of the Cre-lox system, we generated and characterized mice in which fragile X mental retardation protein is selectively deleted or exclusively expressed in astrocytes. We performed in vivo two-photon imaging to track spine dynamics/morphology along dendrites of neurons in the motor cortex and examined associated behavioral defects. Results We found that adult astrocyte-specific Fmr1 KO mice displayed increased spine density in the motor cortex and impaired motor-skill learning. The learning defect coincided with a lack of enhanced spine dynamics in the motor cortex that normally occurs in response to motor skill acquisition. Although spine density was normal at 1 month of age in astrocyte-specific Fmr1 KO mice, new spines formed at an elevated rate. Furthermore, fragile X mental retardation protein expression in only astrocytes was insufficient to rescue most spine or behavioral defects. Conclusions Our work suggests a joint astrocytic-neuronal contribution to FXS pathogenesis and reveals that heightened spine formation during adolescence precedes the overabundance of spines and behavioral defects found in adult Fmr1 KO mice.

Original languageEnglish (US)
Pages (from-to)139-149
Number of pages11
JournalBiological Psychiatry
Volume82
Issue number2
DOIs
StatePublished - Jul 15 2017
Externally publishedYes

Keywords

  • Astrocytes
  • Dendritic spines
  • Fmr1
  • Fragile X syndrome
  • Motor cortex
  • Motor learning

ASJC Scopus subject areas

  • Biological Psychiatry

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