CB1 receptor inhibition restores synaptoneurosomal alternative splicing landscape in fragile X syndrome mice

Fragile X syndrome (FXS), the most frequent heritable cause of intellectual disability and autism, involves impaired cognition and synaptic plasticity. Preclinical studies show that inhibition of the cannabinoid type-1 receptor (CB1R) restores key phenotypic traits in Fmr1 knockout (FX) mice. However, the underlying molecular mechanisms remain undefined. We analyzed the hippocampal synaptoneurosomal transcriptome and confirmed that synaptoneurosomes are an accurate representation of synaptic composition and function. Then, we analyzed this transcriptome after pharmacological CB1R inhibition in male FX mice and found that rimonabant had limited impact at the gene expression level. Notably, detailed in silico analysis of alternative splicing (AS) revealed that rimonabant reverts numerous AS events in FX mice to wild-type levels. These changes in synaptoneurosomal AS landscape suggest a novel mechanism by which CB1R targeting may restore specific AS patterns. Altogether, our results reveal new molecular alterations in FXS context that are sensitive to pharmacological treatment related to cognitive alleviation.