NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism
Shichun Tu (),
Mohd Waseem Akhtar,
Rosa Maria Escorihuela,
Alejandro Amador-Arjona,
Vivek Swarup,
James Parker,
Jeffrey D. Zaremba,
Timothy Holland,
Neha Bansal,
Daniel R. Holohan,
Kevin Lopez,
Scott D. Ryan,
Shing Fai Chan,
Li Yan,
Xiaofei Zhang,
Xiayu Huang,
Abdullah Sultan,
Scott R. McKercher,
Rajesh Ambasudhan,
Huaxi Xu,
Yuqiang Wang,
Daniel H. Geschwind,
Amanda J. Roberts,
Alexey V. Terskikh,
Robert A. Rissman,
Eliezer Masliah,
Stuart A. Lipton () and
Nobuki Nakanishi ()
Additional contact information
Shichun Tu: Scintillon Institute
Mohd Waseem Akhtar: Scintillon Institute
Rosa Maria Escorihuela: Sanford Burnham Prebys Medical Discovery Institute
Alejandro Amador-Arjona: Sanford Burnham Prebys Medical Discovery Institute
Vivek Swarup: University of California
James Parker: Scintillon Institute
Jeffrey D. Zaremba: Sanford Burnham Prebys Medical Discovery Institute
Timothy Holland: Sanford Burnham Prebys Medical Discovery Institute
Neha Bansal: Sanford Burnham Prebys Medical Discovery Institute
Daniel R. Holohan: Sanford Burnham Prebys Medical Discovery Institute
Kevin Lopez: Scintillon Institute
Scott D. Ryan: Sanford Burnham Prebys Medical Discovery Institute
Shing Fai Chan: Sanford Burnham Prebys Medical Discovery Institute
Li Yan: Sanford Burnham Prebys Medical Discovery Institute
Xiaofei Zhang: Sanford Burnham Prebys Medical Discovery Institute
Xiayu Huang: Sanford Burnham Prebys Medical Discovery Institute
Abdullah Sultan: Scintillon Institute
Scott R. McKercher: Scintillon Institute
Rajesh Ambasudhan: Scintillon Institute
Huaxi Xu: Sanford Burnham Prebys Medical Discovery Institute
Yuqiang Wang: Jinan University College of Pharmacy
Daniel H. Geschwind: University of California
Amanda J. Roberts: The Scripps Research Institute
Alexey V. Terskikh: Sanford Burnham Prebys Medical Discovery Institute
Robert A. Rissman: University of California, San Diego, School of Medicine
Eliezer Masliah: University of California, San Diego, School of Medicine
Stuart A. Lipton: Scintillon Institute
Nobuki Nakanishi: Scintillon Institute
Nature Communications, 2017, vol. 8, issue 1, 1-12
Abstract:
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.
Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01563-8
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DOI: 10.1038/s41467-017-01563-8
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