Bulk endocytosis at neuronal synapses.

Neurotransmitter-containing synaptic vesicle (SV) fusion with the nerve terminal plasma membrane initiates neurotransmission in response to neuronal excitation. Under mild stimulation, the fused vesicular membrane is retrieved via kiss-and-run and/or clathrin-mediated endocytosis, which is sufficient to maintain recycling of SVs. When neurons are challenged with very high stimulation, the number of fused SVs can be extremely high, resulting in significant plasma membrane addition. Under such conditions, a higher capacity retrieval pathway, bulk endocytosis, is activated to redress this large membrane imbalance. Despite first being described more than 40 years ago, the molecular mechanisms underpinning this important process have yet to be clearly defined. In this review, we highlight the current evidence for bulk endocytosis and its prevalence in various neuronal models, as well as discuss the underlying molecular components.