Exocytosis of small synaptic vesicles (SVs) is at the heart of how neurons communicate, by the release of neurotransmitters onto neighboring neurons or muscles. Problems with exocytosis underlie many human diseases, such as schizophrenia or epilepsy. To enable the process to respond rapidly and in a sustainable manner, synaptic vesicle endocytosis (SVE) must retrieve the used, empty SV and recycle it rapidly, to sustain high synaptic transmission rates for more than 1 min. We have been defining the central role of dynamin in the molecular mechanisms of SVE at the synapse. Dynamin is a protein that has multiple functions in biology. Dynamin I (DynI) was the first discovered member of the family of dynamin-like proteins and it functions in all neurons to mediate SV retrieval during stimulus-dependent exocytosis. SVE is a process triggered by dephosphorylation of DynI mediated by the calcium-dependent phosphatase calcineurin. It is reset by DynI phosphorylation by Cdk5. The phosphorylation recruits DynI's main partner, syndapin, to complex with DynI at sites of endocytosis. Loss of DynI function results in a rundown of neurotransmission and a massive depletion of SVs from nerve terminals. This shows that SVE can regulate exocytosis under conditions of high or prolonged stimulation. Further, research has been hampered by the lack of specific small molecule inhibitors to further dissect the SVE pathway. We have developed a range of inhibitors of dynamin's guanosine triphosphatase activity as inhibitors of endocytosis. The drugs originate from distinct chemical classes and they target different domains of the dynamin protein. The drugs therefore have different mechanisms of action. This strategy provides more definitive tools with which the biological roles of dynamin can be explored in better detail. It is expected that the drugs will be widely used by neuroscientists. Because all current antiepileptic drugs target some aspect of the SV cycle to reduce exocytosis, and because SVE also regulates exocytosis, we propose that dynamin inhibitors have the potential to become a new class of anti-epileptic drugs and that they may find other neuropsychiatric applications.
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