Breaking the Synaptic Vesicle Cycle: Mechanistic Insights into Presynaptic Dysfunctions in Epilepsy.

Synaptic dysfunction is a hallmark of many neurological disorders including epilepsy. An increasing number of epilepsy-causing pathogenic variants are being identified in genes encoding presynaptic proteins that affect every step of the synaptic vesicle cycle, from vesicle loading, tethering, docking, priming, calcium sensing, fusing, to recycling. These different molecular dysfunctions result in converging impairment of presynaptic neurotransmitter release, yet lead to diverse epileptic disorders. This review focuses on representative monogenic epileptic disorders caused by pathogenic variants of key presynaptic proteins involved in different stages of the synaptic vesicle cycle: SYN1 (vesicle pool regulation), STXBP1 (vesicle docking, priming, and fusion), and DNM1 (vesicle recycling). We discuss the molecular, synaptic, and circuit mechanisms of these archetypal synaptic vesicle exocytosis and endocytosis-related epilepsies and highlight the diversity and commonality of their presynaptic dysfunctions. We further discuss future avenues of research to better connect distinct presynaptic alterations to epileptogenesis and develop novel therapeutic approaches.