Abstract
Understanding the role of lipids in synapses and the aberrant molecular mechanisms causing the cognitive deficits that characterize most lipidosis is necessary to develop therapies for these diseases. Here we describe sphingomyelin (SM) as a key modulator of the dendritic spine actin cytoskeleton. We show that increased SM levels in neurons of acid sphingomyelinase knock out mice (ASMko), which mimic Niemann Pick disease type A (NPA), result in reduced spine number and size and low levels of filamentous actin. Mechanistically, SM accumulation decreases the levels of metabotropic glutamate receptors type I (mGluR1/5) at the synaptic membrane impairing membrane attachment and activity of RhoA and its effectors ROCK and ProfilinIIa. Pharmacological enhancement of the neutral sphingomyelinase rescues the aberrant molecular and morphological phenotypes in vitro and in vivo and improves motor and memory deficits in ASMko mice. Altogether, these data demonstrate the influence of SM and its catabolic enzymes in dendritic spine physiology and contribute to our understanding of the cognitive deficits of NPA patients, opening new perspectives for therapeutic interventions.Subject Categories Genetics, Gene Therapy & Genetic Disease; Neuroscience
Highlights
Alterations in dendritic spines, protrusions at the postsynaptic membrane that receive most of the excitatory input in the central nervous system (Yuste & Tank, 1996), have been related to many cognitive disorders (Carlisle & Kennedy, 2005)
The number of spines identified with DiI labelling per micrometer of dendrite length was significantly reduced in the layer 1 (L1) of the S1 cortex of acid sphingomyelinase knock out mice (ASMko) brains compared to wt
The work presented here makes three main contributions: (i) describes the aberrant phenotype of dendritic spines in the ASMko mouse, which is a model for Niemann Pick disease type A (NPA); (ii) characterizes the molecular mechanism underlying this aberrant phenotype; (iii) provides with pharmacological strategies to revert the anomalies in vitro and in vivo
Summary
Alterations in dendritic spines, protrusions at the postsynaptic membrane that receive most of the excitatory input in the central nervous system (Yuste & Tank, 1996), have been related to many cognitive disorders (Carlisle & Kennedy, 2005). Much less is known about the role of lipids in these processes. This is especially relevant considering that the remodelling of the postsynaptic membrane, of which lipids are major components, is as remarkable as that of the underlying cytoskeleton in spine plasticity. Further support for a key role of lipids in spine dynamics comes from the fact that genetic defects affecting lipid metabolism, and leading to lipidosis, frequently cause cognitive impairment (Futermann & Van Meer, 2004)
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