Translational modulator ISRIB alleviates synaptic and behavioral phenotypes in Fragile X syndrome

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Fragile X syndrome (FXS) results from the loss of fragile X messenger ribonucleoprotein (FMRP), a key translational regulator.
• FMRP loss disrupts protein synthesis, affecting synaptic function and plasticity, but direct translational modulation for FXS treatment remains unexplored.

Purpose of the Study:

• To investigate the therapeutic potential of the translational modulator, integrated stress response inhibitor (ISRIB), in addressing synaptic and behavioral deficits in FXS.
• To elucidate the impact of FMRP loss on synaptic protein regulation and dendritic spine morphology in FXS models.

Main Methods:

• Utilized *Fmr1* knockout (KO) mouse models to study FXS.
• Administered ISRIB to assess its effects on synaptic protein levels, dendritic spine structure, and social recognition behavior.
• Analyzed protein abundance, specifically PSD-95 and glutamate receptors, and observed dendritic spine morphology.

Main Results:

• FMRP loss leads to dysregulated synaptic protein levels, characterized by increased PSD-95 and reduced glutamate receptor accumulation.
• This dysregulation results in the formation of dense, immature dendritic spines, a hallmark of FXS.
• ISRIB treatment rescued these synaptic deficits and significantly improved social recognition in *Fmr1* KO mice.

Conclusions:

• Targeting core translational mechanisms, such as through ISRIB, holds therapeutic potential for FXS.
• These findings suggest that modulating protein synthesis offers a promising strategy for treating FXS and other neurodevelopmental disorders.