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Translational profiling of stress-induced neuroplasticity in the CA3 pyramidal neurons of BDNF Val66Met mice

Molecular Psychiatry volume 23, pages 904–913 (2018)Cite this article

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Abstract

Genetic susceptibility and environmental factors (such as stress) can interact to affect the likelihood of developing a mood disorder. Stress-induced changes in the hippocampus have been implicated in mood disorders, and mutations in several genes have now been associated with increased risk, such as brain-derived neurotrophic factor (BDNF). The hippocampus has important anatomical subdivisions, and pyramidal neurons of the vulnerable CA3 region show significant remodeling after chronic stress, but the mechanisms underlying their unique plasticity remain unknown. This study characterizes stress-induced changes in the in vivo translating mRNA of this cell population using a CA3-specific enhanced green fluorescent protein (EGFP) reporter fused to the L10a large ribosomal subunit (EGFPL10a). RNA-sequencing after isolation of polysome-bound mRNAs allows for cell-type-specific, genome-wide characterization of translational changes after stress. The data demonstrate that acute and chronic stress produce unique translational profiles and that the stress history of the animal can alter future reactivity of CA3 neurons. CA3-specific EGFPL10a mice were then crossed to the stress-susceptible BDNF Val66Met mouse line to characterize how a known genetic susceptibility alters both baseline translational profiles and the reactivity of CA3 neurons to stress. Not only do Met allele carriers exhibit distinct levels of baseline translation in genes implicated in ion channel function and cytoskeletal regulation, but they also activate a stress response profile that is highly dissimilar from wild-type mice. Closer examination of genes implicated in the mechanisms of neuroplasticity, such as the NMDA and AMPA subunits and the BDNF pathway, reveal how wild-type mice upregulate many of these genes in response to stress, but Met allele carriers fail to do so. These profiles provide a roadmap of stress-induced changes in a genetically homogenous population of hippocampal neurons and illustrate the profound effects of gene–environment interactions on the translational profile of these cells.

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Acknowledgements

This project was supported by NIH/F32 MH102065 to JDG, NIH/RO1 MH41256 and the Hope for Depression Research Foundation grant RGA#13-004 to BSM, the Pritzker Consortium and NIH/ R01 NS052819 to FSL, and Brain & Behavior Research Foundation NARSAD Young Investigator Grant 21464, the van Ameringen Foundation and NIH/NINDS R01NS091722 to EFS.

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  1. Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA

    J D Gray, J F Kogan, J Marrocco & B S McEwen

  2. Albert Einstein College of Medicine, Bronx, NY, USA

    T G Rubin

  3. Linkoping University, Linkoping, Sweden

    J Weidmann & S Lindkvist

  4. Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, New York, NY, USA

    F S Lee

  5. Department of Psychiatry, Weill Cornell Medical College, New York, NY, USA

    F S Lee

  6. Laboratory of Molecular Biology, The Rockefeller University, New York, NY, USA

    E F Schmidt

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Gray, J., Rubin, T., Kogan, J. et al. Translational profiling of stress-induced neuroplasticity in the CA3 pyramidal neurons of BDNF Val66Met mice. Mol Psychiatry 23, 904–913 (2018). https://doi.org/10.1038/mp.2016.219

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