Abstract
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.
Highlights
Increasing evidence suggests a key role for lipids in the establishment and functionality of synapses
This study revealed a 3-fold increase in SM levels in Acid sphingomyelinase knockout mice (ASMko) synaptosomes compared to wt (176640 and 59617 nmol/mg protein, respectively, mean6SD, n = 3)
Our data, obtained using a variety of experimental approaches including electrophysiological, electron microscopy, biochemical and biophysical analysis, contribute to define the molecular mechanisms involved in synaptic vesicle docking
Summary
Increasing evidence suggests a key role for lipids in the establishment and functionality of synapses. Phosphoinositides [3] and cholesterol [4] regulate the synaptic vesicle cycle. Much still remains to be learned about the mechanisms by which lipids influence synaptic function and about the enzymatic activities regulating their action. This knowledge is essential to understand the molecular mechanisms of cognition and the defects underlying the cognitive impairment that accompany most lipidosis. NPA results from loss of function mutations in the acid sphingomyelinase (ASM) gene leading to severe mental retardation [8]. ASM is the enzyme responsible for the conversion of SM into ceramide in the lysosomes [9]. SM-loaded lysosomes characterize the cells of ASMko mice [10,11]
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