TY  - JOUR
AU  - Ogunmowo, Tyler H
AU  - Hoffmann, Christian
AU  - Patel, Chintan
AU  - Pepper, Renee
AU  - Wang, Han
AU  - Gowrisankaran, Sindhuja
AU  - Idel, Johanna
AU  - Ho, Annie
AU  - Raychaudhuri, Sumana
AU  - Maher, Brady J
AU  - Cooper, Benjamin H
AU  - Milosevic, Ira
AU  - Milovanovic, Dragomir
AU  - Watanabe, Shigeki
TI  - Intersectin and endophilin condensates prime synaptic vesicles for release site replenishment.
JO  - Nature neuroscience
VL  - 28
IS  - 8
SN  - 1097-6256
CY  - New York, NY
PB  - Nature America
M1  - DZNE-2025-00918
SP  - 1649 - 1662
PY  - 2025
AB  - Following synaptic vesicle fusion, vacated release sites are replenished immediately by new vesicles for subsequent neurotransmission. These replacement vesicles are assumed to be located near release sites and used by chance. Here we find in mouse hippocampal excitatory synapses that replacement vesicles are clustered near the active zone where release sites reside by intersectin-1. Specifically, intersectin-1 forms dynamic molecular condensates with endophilin A1 and sequesters vesicles around this region. In the absence of intersectin-1, fewer vesicles cluster within 20 nm of the plasma membrane, and consequently vacated sites cannot be replenished rapidly, leading to synaptic depression. Mutations in intersectin-1 that disrupt endophilin A1 binding result in similar phenotypes. In the absence of endophilin A1, intersectin-1 is mislocalized, and this replacement pool of vesicles cannot be accessed, suggesting that endophilin A1 is needed to mobilize these vesicles. Thus, our work describes the replacement zone within a synapse, where replacement vesicles are stored for replenishment of the release site.
KW  - Animals
KW  - Synaptic Vesicles: metabolism
KW  - Synaptic Vesicles: ultrastructure
KW  - Synaptic Vesicles: physiology
KW  - Mice
KW  - Hippocampus: cytology
KW  - Hippocampus: metabolism
KW  - Adaptor Proteins, Vesicular Transport: metabolism
KW  - Adaptor Proteins, Vesicular Transport: genetics
KW  - Synapses: metabolism
KW  - Synapses: ultrastructure
KW  - Neurons
KW  - Adaptor Proteins, Signal Transducing: metabolism
KW  - Adaptor Proteins, Signal Transducing: genetics
KW  - Synaptic Transmission: physiology
KW  - Mice, Inbred C57BL
KW  - Mutation: genetics
KW  - Adaptor Proteins, Vesicular Transport (NLM Chemicals)
KW  - intersectin 1 (NLM Chemicals)
KW  - endophilin A1 protein, mouse (NLM Chemicals)
KW  - Adaptor Proteins, Signal Transducing (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40629141
C2  - pmc:PMC12321584
DO  - DOI:10.1038/s41593-025-02002-4
UR  - https://pub.dzne.de/record/280240
ER  -