Intersectin and Endophilin condensates prime synaptic vesicles for release site replenishment

Area of Science:

• Neuroscience
• Cell Biology
• Synaptic Physiology

Background:

• Synaptic transmission relies on the rapid replenishment of vesicles at release sites after neurotransmitter release.
• The precise mechanisms and localization of these replacement vesicles remain incompletely understood.

Purpose of the Study:

• To investigate the role of Intersectin-1 in the spatial organization and availability of synaptic vesicles for replenishment.
• To elucidate the molecular interactions governing vesicle localization near release sites.

Main Methods:

• Investigated the localization of synaptic vesicles using super-resolution microscopy in the presence and absence of Intersectin-1.
• Utilized genetic manipulations and specific mutations to disrupt Intersectin-1 and Endophilin A1 interactions.
• Assessed synaptic transmission efficacy through electrophysiological recordings.

Main Results:

• Intersectin-1 forms dynamic molecular condensates with Endophilin A1, clustering replacement vesicles near synaptic release sites.
• Loss of Intersectin-1 leads to a reduction in vesicles within 20 nm of the plasma membrane, impairing replenishment and causing synaptic depression.
• Disruption of Intersectin-1 and Endophilin A1 binding mimics these effects, while Endophilin A1 is required for mobilizing the sequestered vesicles.

Conclusions:

• Identified a specialized physical region at the synapse where Intersectin-1 and Endophilin A1 cooperate to maintain a readily releasable pool of synaptic vesicles.
• This mechanism is critical for sustained neurotransmission by ensuring rapid site replenishment.