Abstract

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.

Details

Title
NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism
Author
Tu, Shichun 1 ; Mohd Waseem Akhtar 1 ; Escorihuela, Rosa Maria 2 ; Amador-Arjona, Alejandro 3 ; Swarup, Vivek 4 ; Parker, James 1   VIAFID ORCID Logo  ; Zaremba, Jeffrey D 3   VIAFID ORCID Logo  ; Holland, Timothy 3 ; Bansal, Neha 3 ; Holohan, Daniel R 3 ; Lopez, Kevin 1 ; Ryan, Scott D 5 ; Chan, Shing Fai 3 ; Li, Yan 3 ; Zhang, Xiaofei 3 ; Huang, Xiayu 6 ; Sultan, Abdullah 1 ; McKercher, Scott R 7 ; Ambasudhan, Rajesh 1 ; Xu, Huaxi 3 ; Wang, Yuqiang 8 ; Geschwind, Daniel H 4 ; Roberts, Amanda J 9 ; Terskikh, Alexey V 3 ; Rissman, Robert A 10 ; Masliah, Eliezer 11 ; Lipton, Stuart A 12 ; Nakanishi, Nobuki 1 

 Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA, USA; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA 
 Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; Departament de PsiquiatriaiMedicina Legal, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain 
 Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA 
 Center for Autism Research and Treatment (CART), University of California, Los Angeles, CA, USA 
 Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada 
 Bioinformatics Core Facility, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA 
 Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA, USA; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; Department of Molecular Medicine and Neuroscience, Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA, USA 
 Institute of New Drug Research, Jinan University College of Pharmacy, Guangzhou, China 
 Department of Neuroscience and Mouse Behavioral Assessment Core, The Scripps Research Institute, La Jolla, CA, USA 
10  Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, USA; Veterans Affairs San Diego Healthcare System, San Diego, CA, USA 
11  Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, USA; National Institute on Aging, NIH, Bethesda, MD, USA 
12  Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA, USA; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; Department of Molecular Medicine and Neuroscience, Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA, USA; Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, USA 
Pages
1-12
Publication year
2017
Publication date
Nov 2017
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1963432469
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.