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NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism

Transcription factor MEF2C regulates multiple genes linked to autism spectrum disorder (ASD), and human MEF2C haploinsufficiency results in ASD, intellectual disability, and epilepsy. However, molecular mechanisms underlying MEF2C haploinsufficiency syndrome remain poorly understood. Here we report...

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Autores principales: Tu, Shichun, Akhtar, Mohd Waseem, Escorihuela, Rosa Maria, Amador-Arjona, Alejandro, Swarup, Vivek, Parker, James, Zaremba, Jeffrey D., Holland, Timothy, Bansal, Neha, Holohan, Daniel R., Lopez, Kevin, Ryan, Scott D., Chan, Shing Fai, Yan, Li, Zhang, Xiaofei, Huang, Xiayu, Sultan, Abdullah, McKercher, Scott R., Ambasudhan, Rajesh, Xu, Huaxi, Wang, Yuqiang, Geschwind, Daniel H., Roberts, Amanda J., Terskikh, Alexey V., Rissman, Robert A., Masliah, Eliezer, Lipton, Stuart A., Nakanishi, Nobuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684358/
https://www.ncbi.nlm.nih.gov/pubmed/29133852
http://dx.doi.org/10.1038/s41467-017-01563-8
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author Tu, Shichun
Akhtar, Mohd Waseem
Escorihuela, Rosa Maria
Amador-Arjona, Alejandro
Swarup, Vivek
Parker, James
Zaremba, Jeffrey D.
Holland, Timothy
Bansal, Neha
Holohan, Daniel R.
Lopez, Kevin
Ryan, Scott D.
Chan, Shing Fai
Yan, Li
Zhang, Xiaofei
Huang, Xiayu
Sultan, Abdullah
McKercher, Scott R.
Ambasudhan, Rajesh
Xu, Huaxi
Wang, Yuqiang
Geschwind, Daniel H.
Roberts, Amanda J.
Terskikh, Alexey V.
Rissman, Robert A.
Masliah, Eliezer
Lipton, Stuart A.
Nakanishi, Nobuki
author_facet Tu, Shichun
Akhtar, Mohd Waseem
Escorihuela, Rosa Maria
Amador-Arjona, Alejandro
Swarup, Vivek
Parker, James
Zaremba, Jeffrey D.
Holland, Timothy
Bansal, Neha
Holohan, Daniel R.
Lopez, Kevin
Ryan, Scott D.
Chan, Shing Fai
Yan, Li
Zhang, Xiaofei
Huang, Xiayu
Sultan, Abdullah
McKercher, Scott R.
Ambasudhan, Rajesh
Xu, Huaxi
Wang, Yuqiang
Geschwind, Daniel H.
Roberts, Amanda J.
Terskikh, Alexey V.
Rissman, Robert A.
Masliah, Eliezer
Lipton, Stuart A.
Nakanishi, Nobuki
author_sort Tu, Shichun
collection PubMed
description Transcription factor MEF2C regulates multiple genes linked to autism spectrum disorder (ASD), and human MEF2C haploinsufficiency results in ASD, intellectual disability, and epilepsy. However, molecular mechanisms underlying MEF2C haploinsufficiency syndrome remain poorly understood. Here we report that Mef2c (+/−)(Mef2c-het) mice exhibit behavioral deficits resembling those of human patients. Gene expression analyses on brains from these mice show changes in genes associated with neurogenesis, synapse formation, and neuronal cell death. Accordingly, Mef2c-het mice exhibit decreased neurogenesis, enhanced neuronal apoptosis, and an increased ratio of excitatory to inhibitory (E/I) neurotransmission. Importantly, neurobehavioral deficits, E/I imbalance, and histological damage are all ameliorated by treatment with NitroSynapsin, a new dual-action compound related to the FDA-approved drug memantine, representing an uncompetitive/fast off-rate antagonist of NMDA-type glutamate receptors. These results suggest that MEF2C haploinsufficiency leads to abnormal brain development, E/I imbalance, and neurobehavioral dysfunction, which may be mitigated by pharmacological intervention.
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spelling pubmed-56843582017-11-17 NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism Tu, Shichun Akhtar, Mohd Waseem Escorihuela, Rosa Maria Amador-Arjona, Alejandro Swarup, Vivek Parker, James Zaremba, Jeffrey D. Holland, Timothy Bansal, Neha Holohan, Daniel R. Lopez, Kevin Ryan, Scott D. Chan, Shing Fai Yan, Li Zhang, Xiaofei Huang, Xiayu Sultan, Abdullah McKercher, Scott R. Ambasudhan, Rajesh Xu, Huaxi Wang, Yuqiang Geschwind, Daniel H. Roberts, Amanda J. Terskikh, Alexey V. Rissman, Robert A. Masliah, Eliezer Lipton, Stuart A. Nakanishi, Nobuki Nat Commun Article Transcription factor MEF2C regulates multiple genes linked to autism spectrum disorder (ASD), and human MEF2C haploinsufficiency results in ASD, intellectual disability, and epilepsy. However, molecular mechanisms underlying MEF2C haploinsufficiency syndrome remain poorly understood. Here we report that Mef2c (+/−)(Mef2c-het) mice exhibit behavioral deficits resembling those of human patients. Gene expression analyses on brains from these mice show changes in genes associated with neurogenesis, synapse formation, and neuronal cell death. Accordingly, Mef2c-het mice exhibit decreased neurogenesis, enhanced neuronal apoptosis, and an increased ratio of excitatory to inhibitory (E/I) neurotransmission. Importantly, neurobehavioral deficits, E/I imbalance, and histological damage are all ameliorated by treatment with NitroSynapsin, a new dual-action compound related to the FDA-approved drug memantine, representing an uncompetitive/fast off-rate antagonist of NMDA-type glutamate receptors. These results suggest that MEF2C haploinsufficiency leads to abnormal brain development, E/I imbalance, and neurobehavioral dysfunction, which may be mitigated by pharmacological intervention. Nature Publishing Group UK 2017-11-14 /pmc/articles/PMC5684358/ /pubmed/29133852 http://dx.doi.org/10.1038/s41467-017-01563-8 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
Tu, Shichun
Akhtar, Mohd Waseem
Escorihuela, Rosa Maria
Amador-Arjona, Alejandro
Swarup, Vivek
Parker, James
Zaremba, Jeffrey D.
Holland, Timothy
Bansal, Neha
Holohan, Daniel R.
Lopez, Kevin
Ryan, Scott D.
Chan, Shing Fai
Yan, Li
Zhang, Xiaofei
Huang, Xiayu
Sultan, Abdullah
McKercher, Scott R.
Ambasudhan, Rajesh
Xu, Huaxi
Wang, Yuqiang
Geschwind, Daniel H.
Roberts, Amanda J.
Terskikh, Alexey V.
Rissman, Robert A.
Masliah, Eliezer
Lipton, Stuart A.
Nakanishi, Nobuki
NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism
title NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism
title_full NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism
title_fullStr NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism
title_full_unstemmed NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism
title_short NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism
title_sort nitrosynapsin therapy for a mouse mef2c haploinsufficiency model of human autism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684358/
https://www.ncbi.nlm.nih.gov/pubmed/29133852
http://dx.doi.org/10.1038/s41467-017-01563-8
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