Synaptic Vesicle Docking: Sphingosine Regulates Syntaxin1 Interaction with Munc18

Consensus exists that lipids must play key functions in synaptic activity but precise mechanistic information is limited. Acid sphingomyelinase knockout mice (ASMko) are a suitable model to address the role of sphingolipids in synaptic regulation as they recapitulate a mental retardation syndrome, Niemann Pick disease type A (NPA), and their neurons have altered levels of sphingomyelin (SM) and its derivatives. Electrophysiological recordings showed that ASMko hippocampi have increased paired-pulse facilitation and post-tetanic potentiation. Consistently, electron microscopy revealed reduced number of docked vesicles. Biochemical analysis of ASMko synaptic membranes unveiled higher amounts of SM and sphingosine (Se) and enhanced interaction of the docking molecules Munc18 and syntaxin1. In vitro reconstitution assays demonstrated that Se changes syntaxin1 conformation enhancing its interaction with Munc18. Moreover, Se reduces vesicle docking in primary neurons and increases paired-pulse facilitation when added to wt hippocampal slices. These data provide with a novel mechanism for synaptic vesicle control by sphingolipids and could explain cognitive deficits of NPA patients.This work was financed by grants from the National Niemann Pick Disease Foundation, Proyecto intramural 200820I144 (CSIC) and SAF2008-01473 (Ministerio de Ciencia e Innovacion) to M.D.L, Telethon-Italy: grants no. GGP02245 to M.D.L. and M.S.P and no. GGP05236A to M.G., FWO-Vlaanderen (G.0405.02) to P.P.V.V., Compagnia di San Paolo (grant 2007) and Regione Piemonte (Ricerca Sanitaria Finalizzata 2006) to M.S.P., and a short-term mobility grant from the Consiglio Nazionale delle Ricerche-Italy to P.G.C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe