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Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models
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 pathophysiolog...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430680/ https://www.ncbi.nlm.nih.gov/pubmed/28455524 http://dx.doi.org/10.1038/s41598-017-01218-0 |
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author | Schreiber, Jadwiga Grimbergen, Laura-Anne Overwater, Iris Vaart, Thijs van der Stedehouder, Jeffrey Schuhmacher, Alberto J. Guerra, Carmen Kushner, Steven A. Jaarsma, Dick Elgersma, Ype |
author_facet | Schreiber, Jadwiga Grimbergen, Laura-Anne Overwater, Iris Vaart, Thijs van der Stedehouder, Jeffrey Schuhmacher, Alberto J. Guerra, Carmen Kushner, Steven A. Jaarsma, Dick Elgersma, Ype |
author_sort | Schreiber, Jadwiga |
collection | PubMed |
description | 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 | Online Article Text |
id | pubmed-5430680 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-54306802017-05-16 Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models Schreiber, Jadwiga Grimbergen, Laura-Anne Overwater, Iris Vaart, Thijs van der Stedehouder, Jeffrey Schuhmacher, Alberto J. Guerra, Carmen Kushner, Steven A. Jaarsma, Dick Elgersma, Ype Sci Rep Article 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. Nature Publishing Group UK 2017-04-28 /pmc/articles/PMC5430680/ /pubmed/28455524 http://dx.doi.org/10.1038/s41598-017-01218-0 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Schreiber, Jadwiga Grimbergen, Laura-Anne Overwater, Iris Vaart, Thijs van der Stedehouder, Jeffrey Schuhmacher, Alberto J. Guerra, Carmen Kushner, Steven A. Jaarsma, Dick Elgersma, Ype Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models |
title | 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_short | 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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430680/ https://www.ncbi.nlm.nih.gov/pubmed/28455524 http://dx.doi.org/10.1038/s41598-017-01218-0 |
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