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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\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1002\/emmm.201302649","type":"journal-article","created":{"date-parts":[[2014,1,21]],"date-time":"2014-01-21T08:05:36Z","timestamp":1390291536000},"page":"398-413","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Pharmacological reversion of sphingomyelin\u2010induced dendritic spine anomalies in a Niemann Pick disease type A mouse model"],"prefix":"10.1038","volume":"6","author":[{"given":"Ana I","family":"Arroyo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola G","family":"Camoletto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Morando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Sassoe\u2010Pognetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Giustetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul P","family":"Van Veldhoven","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward H","family":"Schuchman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria D","family":"Ledesma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,1,21]]},"reference":[{"key":"BFEMMM201302649_CR1","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1016\/S0140-6736(12)61186-6","volume":"380","author":"D van de Beek","year":"2012","unstructured":"van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR (2012) Advances in treatment of bacterial meningitis. 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