PRESYNAPTIC FILOPODIA SYNCHRONIZE NEUROTRANSMITTER RELEASE BY GENERATING CONVECTIVE MEMBRANE FLOW

Synaptic plasticity is the principal mechanism by which neural circuits compute and adapt. Presynaptic plasticity is traditionally regarded as a transient adaptation of the synaptic vesicle fusion and recycling machinery, whereas the role of structural remodelling of synaptic boutons remains unclear. Using fast optical imaging in hippocampal cultures and acute brain slices, combined with zap-and-freeze and serial-section electron microscopy, we uncover a mechanosensitive coupling between presynaptic structural remodelling and synaptic efficacy. We show that dynamic presynaptic filopodia emerge during active synaptic transmission and transiently deform synaptic boutons to enhance structural connectivity. Filopodia formation requires neuronal activity, calcium influx, and actin polymerization, and occurs in intact brain circuits and human brain tissue. Super-resolution imaging combined with mathematical modelling shows that presynaptic filopodia promote synchronous neurotransmitter release during repeated synaptic vesicle fusion by inducing convective in-plane membrane flow that accelerates release-site clearance. Under excessive neuronal activity, this mechanism becomes maladaptive, amplifying network synchrony and seizure activity. Consistent with this, inhibiting filopodia formation reduces seizure severity in both in vitro and in vivo models of acute seizures. These findings reveal that structurally-induced mechanical forces control the timing and strength of presynaptic signaling and contribute to seizure-induced plasticity.