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dc.contributor.authorSchreiber, Jadwiga
dc.contributor.authorGrimbergen, Laura-Anne
dc.contributor.authorOverwater, Iris
dc.contributor.authorVaart, Thijs van der
dc.contributor.authorStedehouder, Jeffrey
dc.contributor.authorSchuhmacher, Alberto J
dc.contributor.authorGuerra, Carmen 
dc.contributor.authorKushner, Steven A
dc.contributor.authorJaarsma, Dick
dc.contributor.authorElgersma, Ype
dc.identifier.citationSci Rep. 2017;7(1):1256.es_ES
dc.description.abstractRASopathies, characterized by germline mutations in genes encoding proteins of the RAS-ERK signaling pathway, show overlapping phenotypes, which manifest themselves with a varying severity of intellectual disability. However, it is unclear to what extent they share the same downstream pathophysiology that underlies the cognitive deficits. Costello syndrome (CS) is a rare RASopathy caused by activating mutations in the HRAS gene. Here we investigated the mechanisms underlying the cognitive deficits of HRas G12V/G12V mice. HRas G12V/G12V mice showed robust upregulation of ERK signaling, neuronal hypertrophy, increased brain volume, spatial learning deficits, and impaired mGluR-dependent long-term depression (LTD). In contrast, long-term potentiation (LTP), which is affected in other RASopathy mouse models was unaffected. Treatment with lovastatin, a HMG-CoA-Reductase inhibitor which has been shown to rescue the behavioral phenotypes of mouse models of NF1 and Noonan syndrome, was unable to restore ERK signaling and the cognitive deficits of HRas G12V/G12V mice. Administration of a potent mitogen-activated protein kinase (MEK) inhibitor rescued the ERK upregulation and the mGluR-LTD deficit of HRas G12V/G12V mice, but failed to rescue the cognitive deficits. Taken together, this study indicates that the fundamental molecular and cellular mechanisms underlying the cognitive aspects of different RASopathies are remarkably distinct, and may require disease specific treatments.es_ES
dc.description.sponsorshipWe thank Dr. Mariano Barbacid for providing the HRasG12V/G12V mice. We thank Mehrnoush Aghadavoud Jolfaei, Minetta Elgersma, Melika Mozaffari, Nanda Keijzer, Behdokht Hosseini, Rianne Kruit and Kate Ekaterina Sytnik for technical support. This research was supported by the Netherlands Organization for Scientific Research (NWO; ZonMw-Vici; Y.E) and ERA-Net Erare-call (Y.E., J.S.). In addition, generation of the HRasG12V/G12V mouse model was supported by grants from Fondo de Investigación Sanitaria (PI11-02529) and Fundación Ramón Areces (FRA 01-09-001) (C.G., A.S).es_ES
dc.publisherNature Publishing Group es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshBrain es_ES
dc.subject.meshCognitive Dysfunction es_ES
dc.subject.meshCostello Syndrome es_ES
dc.subject.meshDepression es_ES
dc.subject.meshDisease Models, Animal es_ES
dc.subject.meshHypertrophy es_ES
dc.subject.meshMAP Kinase Signaling System es_ES
dc.subject.meshMice es_ES
dc.subject.meshNeurons es_ES
dc.subject.meshProto-Oncogene Proteins p21(ras) es_ES
dc.subject.meshMutation, Missense es_ES
dc.titleMechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse modelses_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.contributor.funderFundación Ramón Areces 
dc.contributor.funderInstituto de Salud Carlos III 
dc.relation.publisherversion 10.1038/s41598-017-01218-0.es_ES
dc.identifier.journalScientific reportses_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Oncología Experimentales_ES
dc.rights.accessRightsopen accesses_ES

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Atribución 4.0 Internacional
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