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

Nature Medicine volume 20, pages 1444–1451 (2014)Cite this article

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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 Ca2+-permeable and Ca2+-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.

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Figure 1: Age-dependent deficits in sociability in tTA:CHMP2BIntron5 mice.
Figure 2: Age-dependent changes in expression levels of different glutamate receptor subunits in the cortex of tTA:CHMP2BIntron5 mice.
Figure 3: Functional consequences of altered AMPAR composition in tTA:CHMP2BIntron5 mice.
Figure 4: miR-124 regulates AMPAR subunits in HEK293 cells, and its expression is reduced in the cortex of tTA:CHMP2BIntron5 mice.
Figure 5: miR-124 and AMPAR expression are altered in the frontal cortex of subjects with bvFTD and in cortical neurons derived from iPSC lines from three subjects with bvFTD.
Figure 6: miR-124 expression and Gria2 knockdown in the mPFC partially rescue social deficits in tTA:CHMP2BIntron5 mice.

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Acknowledgements

We thank S. Ordway and Gao lab members for comments, Y. Li and A. Philbrook for help with some experiments, A. Tapper for sharing behavioral test equipment, the Digital Light Microscopy Core at the University of Massachusetts Medical School (UMMS) for assistance with Golgi staining, the UMMS Viral Vector core for help with AAV vectors, and the University of California–San Francisco Neurodegenerative Disease Brain Bank for some human brain tissues. We also thank R. Rademakers for genotyping some human samples in a previous work51 that we used in the current study and A. Chen-Plotkin for sharing published array data38,40. This work was supported by a UMMS startup fund (F.-B.G.), The Consortium for Frontotemporal Dementia Research (W.W.S.) and the US National Institutes of Health (NS057553, NS066586 and NS079725 to F.-B.G.; DA032283 to W.-D.Y.; MH086509 to S.A.; AG023501 and AG19724 to W.W.S.; and AG016574 to D.W.D. and L.P.).

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Author notes

  1. Jamie M Verheyden, Danqiong Sun, Jian Jiao, Schahram Akbarian & Wei-Dong Yao

    Present address: Present addresses: Laboratory of Genetics, University of Wisconsin–Madison, Madison, Wisconsin, USA (J.M.V.), System Biosciences, Mountain View, California (D.S.), NGM Biopharmaceuticals, South San Francisco, California, USA (J.J.), Departments of Psychiatry and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA (S.A.), Departments of Psychiatry and Neuroscience, State University of New York Upstate Medical University, Syracuse, New York, USA (W.-D.Y.).,

Authors and Affiliations

  1. Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Eduardo Gascon, Kelleen Lynch, Sandra Almeida, Hongru Zhou & Fen-Biao Gao

  2. Division of Neurosciences, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA

    Hongyu Ruan & Wei-Dong Yao

  3. Gladstone Institute of Neurological Disease, San Francisco, California, USA

    Jamie M Verheyden, Danqiong Sun & Jian Jiao

  4. Department of Neurology, Memory and Aging Center, University of California, San Francisco, California, USA

    William W Seeley

  5. Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, USA

    Dennis W Dickson & Leonard Petrucelli

  6. Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Mira Jakovcevski & Schahram Akbarian

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  1. Eduardo Gascon
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Contributions

E.G., K.L., S.A. and H.Z. performed most experiments. H.R. and W.-D.Y. carried out the electrophysiology analysis and wrote the relevant sections. J.M.V., D.S. and J.J. generated the transgenic mouse lines. L.P., D.W.D. and W.W.S. provided brain tissues from control subjects and subjects with FTD. M.J. and S.A. assisted with behavioral tests. E.G. and F.-B.G. analyzed the data and wrote the manuscript. F.-B.G. conceived and supervised the project.

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Correspondence to Fen-Biao Gao.

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Gascon, E., Lynch, K., Ruan, H. et al. Alterations in microRNA-124 and AMPA receptors contribute to social behavioral deficits in frontotemporal dementia. Nat Med 20, 1444–1451 (2014). https://doi.org/10.1038/nm.3717

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