Impact de la déficience en FMRP sur les mécanismes présynaptiques à la fibre moussue de l’hippocampe

Fragile X syndrome (FXS), the most common inherited form of intellectual disability and a major cause of autism spectrum disorder, results from silencing of the Fmr1 gene encoding the RNA-binding protein, FMRP. While most research has focused on dendritic and postsynaptic mechanisms, emerging evidence suggests a presynaptic role of FMRP, particularly through cAMP-dependent signaling pathways. This project investigates how loss of FMRP affects presynaptic mechanisms in the CA3 region of the hippocampus, with a specific emphasis on cAMP-protein kinase A (PKA) signaling. Using patch-clamp electrophysiology and imaging in acute and fixed mouse hippocampal slices with targeted genetic mutations in dentate gyrus cells, I show that presynaptic loss of FMRP disrupts mossy fiber-CA3 synaptic transmission. My results indicate a deregulation of cAMP-PKA signaling and altered presynaptic calcium-dependent mechanisms, providing new insights into the presynaptic contribution of FMRP to synaptic function in FXS.