TY - JOUR
T1 - NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism
AU - Tu, Shichun
AU - Akhtar, Mohd Waseem
AU - Escorihuela, Rosa Maria
AU - Amador-Arjona, Alejandro
AU - Swarup, Vivek
AU - Parker, James
AU - Zaremba, Jeffrey D.
AU - Holland, Timothy
AU - Bansal, Neha
AU - Holohan, Daniel R.
AU - Lopez, Kevin
AU - Ryan, Scott D.
AU - Chan, Shing Fai
AU - Yan, Li
AU - Zhang, Xiaofei
AU - Huang, Xiayu
AU - Sultan, Abdullah
AU - McKercher, Scott R.
AU - Ambasudhan, Rajesh
AU - Xu, Huaxi
AU - Wang, Yuqiang
AU - Geschwind, Daniel H.
AU - Roberts, Amanda J.
AU - Terskikh, Alexey V.
AU - Rissman, Robert A.
AU - Masliah, Eliezer
AU - Lipton, Stuart A.
AU - Nakanishi, Nobuki
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85034272754&partnerID=8YFLogxK
U2 - 10.1038/s41467-017-01563-8
DO - 10.1038/s41467-017-01563-8
M3 - Article
C2 - 29133852
AN - SCOPUS:85034272754
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1488
ER -