Author response: A dynamin 1-, dynamin 3- and clathrin-independent pathway of synaptic vesicle recycling mediated by bulk endocytosis

Neurons propagate electrical signals from one cell to the next using small molecules called neurotransmitters. These molecules are held inside small compartments called synaptic vesicles. Once a neuron receives an electrical stimulus, the membranes that enclose the synaptic vesicles fuse with the plasma membrane that encloses the neuron. This releases the neurotransmitters, which then trigger an electrical signal in the neighboring cell. Once the neurotransmitters are released, the vesicle membrane is rapidly reinternalized from the plasma membrane in a process called endocytosis and then recycled, ready for the next round of signal transmission. The process of synaptic vesicle membrane endocytosis and recycling has been studied extensively, and several different mechanisms by which it occurs have been identified. The best understood relies on a protein called clathrin, and is thought to be essential for nervous system function. Recently, however, a mechanism of vesicle membrane endocytosis that does not involve clathrin was identified. This mechanism, called bulk endocytosis, involves reinternalizing large regions of the cell plasma membrane to generate large compartments called vacuoles, from which new synaptic vesicles eventually form. This mechanism has been observed when neurons fire at high frequency. The cellular processes underlying bulk endocytosis are not well understood, although several studies suggest proteins called dynamins are important. Wu et al. simulated the conditions a cell experiences during high levels of activity in neurons that lacked the two major dynamins present at the synapses between neurons—dynamin 1 and dynamin 3. In these neurons, robust bulk endocytosis occurred, suggesting that these two major neuronal dynamins do not play a role in this process. Furthermore, formation of vesicles from the vacuoles generated by bulk endocytosis appeared to be clathrin-independent. These findings point to the occurrence of a pathway of synaptic vesicle recycling that bypasses the need for dynamin 1 and 3 as well as for clathrin. To reconcile these results with previously published work, Wu et al. propose that dynamins may only be required for processes that also require clathrin. But how are vesicles recycled during bulk endocytosis if dynamins are not involved? There are currently few leads to base alternative mechanisms on. Further work is required to unravel this mystery, and to provide insights into how clathrin-dependent and independent recycling processes are linked during high neuronal activity.