Novel presynaptic assay system revealed that metformin ameliorates exaggerated synaptic release and Munc18-1 accumulation in presynapses of neurons from Fragile X syndrome mouse model

Abstract

Fragile X syndrome (FXS) is a developmental disorder characterized by intellectual disability and autistic-like behaviors. These symptoms are supposed to result from dysregulated translation in pre- and postsynapses, resulting in aberrant synaptic plasticity. Although most drug development research on FXS has focused on aberrant postsynaptic functions by excess translation in postsynapses, the effect of drug candidates on FXS in presynaptic release is largely unclear. In this report, we developed a novel assay system using neuron ball culture with beads to induce presynapse formation, allowing for the analysis of presynaptic phenotypes, including presynaptic release. Metformin, which is shown to rescue core phenotypes in FXS mouse model by normalizing dysregulated translation, ameliorated the exaggerated presynaptic release of neurons of FXS model mouse using this assay system. Furthermore, metformin suppressed the excess accumulation of the active zone protein Munc18-1, which is supposed to be locally translated in presynapses. These results suggest that metformin rescues both postsynaptic and presynaptic phenotypes by inhibiting excess translation in FXS neurons.