Presynaptic alterations in the brain of a murine model of Niemann-Pick disease

Niemann-Pick disease (NPD) type A is a severe neurodegenerative disorder that has no cure, causes mental retardation and leads to death by 3-4 years of age. It is caused by deficient activity of acid sphingomyelinase (ASM), a lysosomal enzyme that hydrolyzes sphingomyelin into ceramide and phosphocoline. Here, we used ASM-KO mice to analyse the effects of the disorder on synapse structure, function and plasticity. Biochemical analysis of synaptosomal preparations revealed increased levels of sphingomyelin, but not other lipids, in the plasma membrane of ASM-KO mice. In vitro electrophysiological recordings of basal synaptic transmission in hippocampal slices (CA1, stratum radiatum) showed similar input-output responses in control and ASM-KO mice. However, ASM mutants showed an evident increase in paired-pulse facilitation and post-tetanic potentiation, whereas synaptic depression during high-frequency stimulation and long-term potentiation were normal. Notably, application of exogenous sphingomyelin (200 µg/ml) to slices of WT mice partially mimicked the effects of ASM gene deletion. Electron microscopic analyses revealed no variations in axospinous synapse density in hippocampal stratum radiatum of mutant mice. However, the size of pre- and post-synaptic profiles and the length of the post-synaptic density were considerably smaller in ASM-KO mice with respect to controls. In addition, the number and density of docked vesicles were markedly reduced in presynaptic varicosities of ASM mutants. Taken together, these results indicate that the accumulation of sphingomyelin in synaptic specializations may account for the observed alterations of the structure and short-term plasticity of axospinous synapses that may underlie the neurological deficits associated with NPD.