NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism.

Autor: Tu S; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA, 92121, USA. shichuntu@scintillon.org.; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA. shichuntu@scintillon.org., Akhtar MW; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA, 92121, USA.; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Escorihuela RM; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.; Departament de PsiquiatriaiMedicina Legal, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain., Amador-Arjona A; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Swarup V; Center for Autism Research and Treatment (CART), University of California, Los Angeles, CA, 90095, USA., Parker J; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA, 92121, USA.; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Zaremba JD; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Holland T; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Bansal N; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Holohan DR; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Lopez K; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA, 92121, USA.; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Ryan SD; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.; Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada, N1G 2W1., Chan SF; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Yan L; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Zhang X; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Huang X; Bioinformatics Core Facility, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Sultan A; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA, 92121, USA.; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., McKercher SR; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA, 92121, USA.; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.; Department of Molecular Medicine and Neuroscience, Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA, 92037, USA., Ambasudhan R; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA, 92121, USA.; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Xu H; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Wang Y; Institute of New Drug Research, Jinan University College of Pharmacy, Guangzhou, 510632, China., Geschwind DH; Center for Autism Research and Treatment (CART), University of California, Los Angeles, CA, 90095, USA., Roberts AJ; Department of Neuroscience and Mouse Behavioral Assessment Core, The Scripps Research Institute, La Jolla, CA, 92037, USA., Terskikh AV; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Rissman RA; Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA.; Veterans Affairs San Diego Healthcare System, San Diego, CA, 92161, USA., Masliah E; Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA.; National Institute on Aging, NIH, Bethesda, MD, 20892, USA., Lipton SA; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA, 92121, USA. slipton@scripps.edu.; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA. slipton@scripps.edu.; Department of Molecular Medicine and Neuroscience, Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA, 92037, USA. slipton@scripps.edu.; Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA. slipton@scripps.edu., Nakanishi N; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA, 92121, USA. nnakanishi@scintillon.org.; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA. nnakanishi@scintillon.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2017 Nov 14; Vol. 8 (1), pp. 1488. Date of Electronic Publication: 2017 Nov 14.
DOI: 10.1038/s41467-017-01563-8
Abstrakt: 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.
Databáze: MEDLINE