Greasing the synaptic vesicle cycle by membrane lipids

• Lipids function as key regulators of neurotransmission.
• Cholesterol may serve as a membrane organizer during synaptic vesicle exo- and endocytosis.
• Sphingolipids and their metabolites may regulate synaptic vesicle exo-endocytosis.
• Phosphoinositides act as protein-recruitment hubs potentially coupling exo- and endocytosis at synapses.

Neurotransmission is based on the exocytic release of neurotransmitters from synaptic vesicles (SVs) at nerve terminals and the subsequent retrieval of SV membranes. Evidence from genetic analysis of model organisms, high-resolution imaging, and biochemical studies indicate that, in addition to the well-studied function of exo-endocytic protein networks, membrane lipids and their derivatives play a key role in SV cycling. These include structural lipids such as cholesterol and sphingolipids as well as phosphoinositides (PIs), which interact with select components of the exocytic and endocytic machineries, thereby coupling both limbs of the SV cycle. Here we provide an overview of the function of lipids in SV cycling and discuss potential models of how lipids and lipid–protein interactions may regulate presynaptic function.