| Popis: |
Funding Information: We thank Marisa Brockmann and Gülcin Vardar for initial help with SynGCamp6f imaging and electrophysiology, respectively. We thank Katja Pötschke, Bettina Brokowski, Heike Lerch, Nadine Albrecht-Koepke, and Berit Söhl-Kielczynski for expert technical assistance and the Viral Core Facility of the Charité – Universitätsmedizin Berlin for lentivirus and AAV production. We thank the Core Facility for Electron Microscopy of the Charité for their support with the electron microscope. This study was supported by the Charité Universitätsmedizin Berlin (M.W.-B., J.K., T.T., C.R.), the German Research Council via a Reinhart Koselleck project (C.R.), the Lydia Rabinowitsch-Förderung (M.W.-B.), the Academy of Finland (grant 3222647 to V.M.O.), and the Sigrid Jusélius Foundation (V.M.O.). Publisher Copyright: © 2022 The Authors Cholesterol is crucial for neuronal synaptic transmission, assisting in the molecular and structural organization of lipid rafts, ion channels, and exocytic proteins. Although cholesterol absence was shown to result in impaired neurotransmission, how cholesterol locally traffics and its route of action are still under debate. Here, we characterized the lipid transfer protein ORP2 in murine hippocampal neurons. We show that ORP2 preferentially localizes to the presynapse. Loss of ORP2 reduces presynaptic cholesterol levels by 50%, coinciding with a profoundly reduced release probability, enhanced facilitation, and impaired presynaptic calcium influx. In addition, ORP2 plays a cholesterol-transport-independent role in regulating vesicle priming and spontaneous release, likely by competing with Munc18-1 in syntaxin1A binding. To conclude, we identified a dual function of ORP2 as a physiological modulator of the synaptic cholesterol content and a regulator of neuronal exocytosis. |
