NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism
Tu, Shichun (Sanford Burnham Prebys Medical Discovery Institute. Neuroscience and Aging Research Center)
Akhtar, Mohd Waseem (Sanford Burnham Prebys Medical Discovery Institute. Neuroscience and Aging Research Center)
Escorihuela, Rosa M (Universitat Autònoma de Barcelona. Departament de Psiquiatria i de Medicina Legal)
Amador-Arjona, Alejandro (Sanford Burnham Prebys Medical Discovery Institute. Neuroscience and Aging Research Center)
Swarup, Vivek (University of California. Center for Autism Research and Treatment (CART))
Parker, James (Sanford Burnham Prebys Medical Discovery Institute. Neuroscience and Aging Research Center)
Zaremba, Jeffrey D. (Sanford Burnham Prebys Medical Discovery Institute. Neuroscience and Aging Research Center)
Holland, Timothy (Sanford Burnham Prebys Medical Discovery Institute. Neuroscience and Aging Research Center)
Bansal, Neha (Sanford Burnham Prebys Medical Discovery Institute. Neuroscience and Aging Research Center)
Holohan, Daniel R. (Sanford Burnham Prebys Medical Discovery Institute. Neuroscience and Aging Research Center)
Lopez, Kevin (Sanford Burnham Prebys Medical Discovery Institute. Neuroscience and Aging Research Center)
Ryan, Scott D. (Department of Molecular and Cellular Biology, University of Guelph, Guelph, Canada)
Chan, Shing Fai (Sanford Burnham Prebys Medical Discovery Institute. Neuroscience and Aging Research Center)
Yan, Li (Sanford Burnham Prebys Medical Discovery Institute. Neuroscience and Aging Research Center)
Zhang, Xiaofei (Sanford Burnham Prebys Medical Discovery Institute. Neuroscience and Aging Research Center)
Huang, Xiayu (Sanford Burnham Prebys Medical Discovery Institute. Bioinformatics Core Facility)
Sultan, Abdullah (Sanford Burnham Prebys Medical Discovery Institute. Neuroscience and Aging Research Center)
McKercher, Scott R. (The Scripps Research Institute. Department of Molecular Medicine and Neuroscience, Neuroscience Translational Center)
Ambasudhan, Rajesh (Sanford Burnham Prebys Medical Discovery Institute. Neuroscience and Aging Research Center)
Xu, Huaxi (Sanford Burnham Prebys Medical Discovery Institute. Neuroscience and Aging Research Center)
Wang, Yuqiang (Jinan University College of Pharmacy. Institute of New Drug Research)
Geschwind, Daniel H. (University of California. Center for Autism Research and Treatment (CART))
Roberts, Amanda J. (The Scripps Research Institute. Department of Neuroscience and Mouse Behavioral Assessment Core)
Terskikh, Alexey V. (Sanford Burnham Prebys Medical Discovery Institute. Neuroscience and Aging Research Center)
Rissman, Robert A. (Veterans Affairs San Diego Healthcare System)
Masliah, Eliezer (Department of Neurosciences, University of California)
Lipton, Stuart A. (University of California, San Diego, School of Medicine. Department of Neurosciences)
Nakanishi, Nobuki (Sanford Burnham Prebys Medical Discovery Institute. Neuroscience and Aging Research Center)

Data:	2017
Resum:	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.
Ajuts:	Agència de Gestió d'Ajuts Universitaris i de Recerca 2010 BE1 00954
Nota:	Altres ajuts: NIH: P01 HD029587, R01 NS086890, R01 AG056259, RF1 AG057409, DP1 DA041722, R43 AG052233, R43 AG055208, R21 AG048519; Department of Defense (Army) W81XWH, W81XWH-09-1-0229
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Nature communications, Vol. 8 (november 2017) , ISSN 2041-1723

DOI: 10.1038/s41467-017-01563-8
PMID: 29133852

12 p, 4.1 MB

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