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The fragile X mutation impairs homeostatic plasticity in human neurons by blocking synaptic retinoic acid signaling

Zhenjie Zhang1, Samuele G Marro2,3, Yingsha Zhang4

  • 1Departments of Neurosurgery, and Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305-5453, USA.

Science Translational Medicine
|August 3, 2018
PubMed

Insights

Fragile X syndrome (FXS) results from the fragile X mental retardation 1 (FMR1) gene's inactivation. Loss of FMR1 function impairs homeostatic synaptic plasticity by blocking retinoic acid signaling, contributing to neuronal dysfunction in FXS.

Area of Science:

  • Neuroscience
  • Genetics
  • Developmental Biology

Background:

  • Fragile X syndrome (FXS) is a leading genetic cause of intellectual disability.
  • FXS arises from the inactivation of the fragile X mental retardation 1 (FMR1) gene.
  • The precise mechanisms linking FMR1 inactivation to FXS pathophysiology are not fully understood.

Purpose of the Study:

  • To investigate the role of FMR1 in synaptic plasticity in human neurons.
  • To elucidate the molecular pathways affected by FMR1 inactivation in FXS.
  • To explore the potential of patient-derived neurons for FXS research.

Main Methods:

  • Generation of human neurons from induced pluripotent stem cells (iPSCs) of FXS patients and controls.
  • Utilized embryonic stem cells with conditional FMR1 mutations.
  • Assessed homeostatic synaptic plasticity and basal synaptic transmission.
  • Investigated the role of retinoic acid signaling in synaptic regulation.

Main Results:

  • Loss of FMR1 function specifically abolished homeostatic synaptic plasticity.
  • Homeostatic plasticity in human neurons is mediated by retinoic acid, regulating synaptic strength.
  • FMR1 inactivation disrupted retinoic acid-mediated synaptic regulation.
  • Repairing the FMR1 mutation restored FMRP expression and rescued retinoic acid signaling.

Conclusions:

  • FMR1 inactivation causes a specific deficit in homeostatic synaptic plasticity via impaired retinoic acid signaling.
  • This impairment may contribute to the neuronal dysfunction observed in Fragile X syndrome.
  • FXS patient-derived iPSC neurons offer a valuable model for studying FXS mechanisms.

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