Synaptic transcriptomic changes sensitive to pharmacological approaches in fragile X syndrome: from mouse to human

Fragile X syndrome (FXS), the most common monogenic cause of intellectual disability and autism, is characterized by impairment in cognitive function and synaptic plasticity. Several preclinical studies in animal models of FXS indicate that key cognitive alterations may be alleviated by pharmacological interventions directed to neurotransmitter systems and intracellular signaling cascades. However, the molecular outcome underlying the effectiveness of these potential treatments that share the alleviation of memory deficits are poorly understood. We studied the hippocampal synaptic transcriptome to identify potential molecular outcomes of different relevant treatments in FXS. As a result, we pinpointed the alternative splicing (AS) of synaptic RNAs as a cellular process responsive to systemic endocannabinoid system modulation and phosphodiesterase 4D inhibition. Moreover, we revealed that memory rescue by peripheral cannabinoid type-1 receptor inhibition depends on peripheral β-adrenergic and serotonergic mechanisms. Finally, we determined the importance of AS modifications in the synaptic transcriptome of subjects with FXS. Altogether, we provided additional insights into the molecular phenotype of FXS, and its modulation associated to memory improvement.