Revisiting the Role of Clathrin-Mediated Endoytosis in Synaptic Vesicle Recycling

Abstract

Without robust mechanisms to efficiently form new synaptic vesicles (SVs), the tens to hundreds of SVs typically present at the neuronal synapse would be rapidly used up, even at modest levels of neuronal activity. SV recycling is thus critical for synaptic physiology and proper function of sensory and nervous systems. Yet, more than four decades after it was originally proposed that the SVs are formed and recycled locally at the presynaptic terminals, the mechanisms of endocytic processes at the synapse are heavily debated. Clathrin-mediated endocytosis, a type of endocytosis that capitalizes on the clathrin coat, a number of adaptor and accessory proteins, and the GTPase dynamin, is well understood, while the contributions of clathrin-independent fast endocytosis, kiss-and-run, bulk endocytosis and ultrafast endocytosis are still being evaluated. This review article revisits and summarizes the current knowledge on the SV reformation with a focus on clathrin-mediated endocytosis, and it discusses the modes of SV formation from endosome-like structures at the synapse. Given the importance of this topic, future advances in this active field are expected to contribute to better comprehension of neurotransmission, and to have general implications for neuroscience and medicine.

Keywords: clathrin; dyanmin; endocytosis; endophilin; endosomes; fast endocytosis; synaptic transmission; synaptic vesicle size.

Figure 1

Schematic representation of the synaptic vesicle (SV) dynamics at the presynaptic terminal. SVs that accumulate at the presynaptic terminal originate from various sources: they are either actively transported to the synapses or recycled locally, either in the close proximity to the active zone (periactive zone) or budding from endosome-like structures. Furthermore, significant exchange of SVs happens between adjacent synapses. Active zone is depicted in dark yellow, SVs in orange, clathrin coated vesicles (CCVs) in dark brown and endosome-like structure in light-brown color.

Figure 2

Model of clathrin-mediated endocytosis, a form of endocytosis that builds on the clathrin coat, the GTPase dynamin, and a variety of accessory factors, like clathrin adaptors, BAR proteins (e.g., endophilin) and lipid phosphatases (e.g., synaptojanin-1).

Figure 3

Modes of SV recovery from endosome-like structures. (A) Clathrin-mediated budding. (B) Fusion of endosome-like structures with the plasma membrane (a sort of homotypic fusion of bulk internalized plasma membrane fragments) followed by subsequent recovery of SV proteins from the plasma membrane by clathrin-mediated endocytosis. (C) Budding by clathrin-independent mechanisms but mediated by some coat proteins. (D) Tubulation followed by tubule fragmentation without classic coat proteins. Endosome-like structures are depicted in brown and clathin coat in green. Black lines outline the membrane contours, and blue dotted line represents clathrin-independent coat.