Synaptic vesicle (SV) recycling is essential for the maintenance of neurotransmission, with a number of neurodevelopmental disorders linked to defects in this process. Fragile X syndrome (FXS) results from a loss of fragile X mental retardation protein (FMRP) encoded by the FMR1 gene. FMRP is an established translation repressor, however it also has translation-independent presynaptic roles, including regulation of the trafficking and function of specific ion channels. Since defects in SV recycling are exacerbated during intense neuronal activity, we investigated whether these events were disproportionately affected by the absence of FMRP. We revealed that primary neuronal cultures from a Fmr1 knockout rat model display a specific defect in activity-dependent bulk endocytosis (ADBE). ADBE is dominant during intense neuronal activity, and this defect resulted in an inability of Fmr1 knockout neurons to sustain SV recycling during trains of high frequency stimulation. Using a molecular replacement strategy, we revealed that a human FMRP interaction mutant failed to correct ADBE dysfunction in knockout neurons. Therefore, FMRP performs a key role in sustaining neurotransmitter release via selective control of the endocytosis mode, ADBE.
bioRxiv Subject Collection: Neuroscience