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NitroSynapsin Therapy for a Mouse MEF2C Haploinsufficiency Model of Human Autism

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, etc.

Nat Commun. 2017 Nov 14;8(1):1488.

PMID: 29133852

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP351329889	Memantine Related Compound E		351329-88-9	Price

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