Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models

Abstract RASopathies, 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 patho...

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Autores principales:	Jadwiga Schreiber, Laura-Anne Grimbergen, Iris Overwater, Thijs van der Vaart, Jeffrey Stedehouder, Alberto J. Schuhmacher, Carmen Guerra, Steven A. Kushner, Dick Jaarsma, Ype Elgersma
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Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e97ef2c4374149b689e3417c7b683ad5
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spelling	oai:doaj.org-article:e97ef2c4374149b689e3417c7b683ad52021-12-02T11:41:21ZMechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models10.1038/s41598-017-01218-02045-2322https://doaj.org/article/e97ef2c4374149b689e3417c7b683ad52017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01218-0https://doaj.org/toc/2045-2322Abstract RASopathies, 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.Jadwiga SchreiberLaura-Anne GrimbergenIris OverwaterThijs van der VaartJeffrey StedehouderAlberto J. SchuhmacherCarmen GuerraSteven A. KushnerDick JaarsmaYpe ElgersmaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-19 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jadwiga Schreiber Laura-Anne Grimbergen Iris Overwater Thijs van der Vaart Jeffrey Stedehouder Alberto J. Schuhmacher Carmen Guerra Steven A. Kushner Dick Jaarsma Ype Elgersma Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models
description	Abstract RASopathies, 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.
format	article
author	Jadwiga Schreiber Laura-Anne Grimbergen Iris Overwater Thijs van der Vaart Jeffrey Stedehouder Alberto J. Schuhmacher Carmen Guerra Steven A. Kushner Dick Jaarsma Ype Elgersma
author_facet	Jadwiga Schreiber Laura-Anne Grimbergen Iris Overwater Thijs van der Vaart Jeffrey Stedehouder Alberto J. Schuhmacher Carmen Guerra Steven A. Kushner Dick Jaarsma Ype Elgersma
author_sort	Jadwiga Schreiber
title	Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models
title_short	Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models
title_full	Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models
title_fullStr	Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models
title_full_unstemmed	Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models
title_sort	mechanisms underlying cognitive deficits in a mouse model for costello syndrome are distinct from other rasopathy mouse models
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e97ef2c4374149b689e3417c7b683ad5
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Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models

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