Alterations in microRNA-124 and AMPA receptors contribute to social behavioral deficits in frontotemporal dementia

Eduardo Gascon, Kelleen Lynch, Hongyu Ruan, Sandra Almeida, Jamie M. Verheyden, William W. Seeley, Dennis W. Dickson, Leonard Petrucelli, Danqiong Sun, Jian Jiao, Hongru Zhou, Mira Jakovcevski, Schahram Akbarian, Wei Dong Yao, Fen Biao Gao

Research output: Contribution to journalArticle

101 Scopus citations

Abstract

Neurodegenerative diseases, such as frontotemporal dementia (FTD), are often associated with behavioral deficits, but the underlying anatomical and molecular causes remain poorly understood. Here we show that forebrain-specific expression of FTD-associated mutant CHMP2B in mice 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 an imbalance between Ca 2+-permeable and Ca 2+-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 the cerebral cortex of mice expressing the mutant CHMP2B. We found similar changes in miR-124 and AMPAR levels in the frontal cortex and induced pluripotent stem cell-derived neurons from subjects with behavioral variant FTD. Moreover, ectopic miR-124 expression in the medial prefrontal cortex of mutant mice decreased AMPAR levels and partially rescued behavioral deficits. Knockdown of the AMPAR subunit Gria2 also alleviated social impairments. Our results identify a previously undescribed mechanism involving miR-124 and AMPARs in regulating social behavior in FTD and suggest a potential therapeutic avenue.

Original languageEnglish (US)
Pages (from-to)1444-1451
Number of pages8
JournalNature Medicine
Volume20
Issue number12
DOIs
StatePublished - Dec 1 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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