Gascon, EduardoLynch, KelleenRuan, HongyuAlmeida, SandraVerheyden, JamieSeeley, William W.Dickson, Dennis W.Petrucelli, LeonardSun, DanqiongJiao, JianZhou, HongruJakovcevski, MiraAkbarian, SchahramYao, Wei-DongGao, Fen-Biao2015-07-132014Gascon, E., K. Lynch, H. Ruan, S. Almeida, J. Verheyden, W. W. Seeley, D. W. Dickson, et al. 2014. “Alterations in microRNA-124 and AMPA receptors contribute to social behavioral deficits in frontotemporal dementia.” Nature medicine 20 (12): 1444-1451. doi:10.1038/nm.3717. http://dx.doi.org/10.1038/nm.3717.1078-8956http://nrs.harvard.edu/urn-3:HUL.InstRepos:17295754Many neurodegenerative diseases, such as frontotemporal dementia (FTD), are associated with behavioral deficits, but the anatomical and molecular bases remain poorly understood. Here we show that forebrain-specific expression of FTD-associated mutant CHMP2B causes several age-dependent neurodegenerative phenotypes, including social behavioral impairments. The social deficits were accompanied by a change in AMPA receptor (AMPAR) composition, leading to imbalance between Ca2+-permeable and -impermeable AMPARs. Expression of most AMPAR subunits was regulated by the brain-enriched microRNA (miR-124), whose abundance was markedly decreased in the superficial layers of cerebral cortex of FTD mice. We found similar changes in miR-124 and AMPAR levels in the frontal cortex and iPSC-derived neurons of subjects with behavioral variant FTD. Moreover, miR-124 expression in the medial prefrontal cortex decreased AMPAR levels and partially rescued behavioral deficits. Knockdown of Gria2 also alleviated social impairments in FTD mice. Our results identify a novel mechanism involving miR-124 and AMAPRs in regulating social behavior in FTD and suggest a potential therapeutic avenue.en-USAMPA receptorCHMP2Bfrontotemporal dementiamicroRNAneurodegenerationsocial behaviorJournal Article2015-07-1310.1038/nm.3717