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Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior

Molecular Psychiatry volume 18, pages 993–1005 (2013)Cite this article

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Abstract

Glucocorticoids (GCs) secreted after stress reduce adult hippocampal neurogenesis, a process that has been implicated in cognitive aspects of psychopathology, amongst others. Yet, the exact role of the GC receptor (GR), a key mediator of GC action, in regulating adult neurogenesis is largely unknown. Here, we show that GR knockdown, selectively in newborn cells of the hippocampal neurogenic niche, accelerates their neuronal differentiation and migration. Strikingly, GR knockdown induced ectopic positioning of a subset of the new granule cells, altered their dendritic complexity and increased their number of mature dendritic spines and mossy fiber boutons. Consistent with the increase in synaptic contacts, cells with GR knockdown exhibit increased basal excitability parallel to impaired contextual freezing during fear conditioning. Together, our data demonstrate a key role for the GR in newborn hippocampal cells in mediating their synaptic connectivity and structural as well as functional integration into mature hippocampal circuits involved in fear memory consolidation.

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Acknowledgements

We thank R van der Sluis, M Ichwan, ICM Bakker and J Shi (LACDR, Leiden), and Ruben Eggers (NIN, Amsterdam), for excellent technical assistance; Drs S Jessberger and K Lukowiak for critically reading, and Dr SA Fratantoni for critical revisions of the manuscript. The research presented in this article was supported by grants from The Netherlands Technology Foundation (STW), the Applied Science Division of the Netherlands Scientific Organization, the Technology Program of the Netherlands Ministry of Economic affairs (LFA6332) and The Center for Medical System Biology, Leiden, The Netherlands (to EV); HersenStichting Nederland and ISAO (to PJL); and VIDI H64.09.016 from the Netherlands Organization for Scientific Research (NOW; to CPF).

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  1. C P Fitzsimons and L W A van Hooijdonk: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Pharmacology, Leiden University Medical Center/Leiden Amsterdam Center for Drug Research, Leiden, The Netherlands

    C P Fitzsimons, L W A van Hooijdonk, I Zalachoras, V Brinks, T G Schouten, D J Saaltink, T Dijkmans, E R de Kloet, O C Meijer, M S Oitzl & E Vreugdenhil

  2. Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands

    C P Fitzsimons, M Schouten & P J Lucassen

  3. Department of Neurosurgery, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL, USA

    T Zheng & D A Steindler

  4. Laboratory for Neuroregeneration, Netherlands Institute for Neuroscience, Royal Academy of Arts and Sciences, Amsterdam, The Netherlands

    J Verhaagen

  5. Leiden Institute for Advanced Computer Sciences (LIACS), Leiden University, Leiden, The Netherlands

    F J Verbeek

  6. Division Neuroscience, Rudolf Magnus Institute, UMC, Utrecht, The Netherlands

    H Karst & M Joels

  7. Department of Human Genetics, Migraine Research Group, Leiden University Medical Centre, Leiden, The Netherlands

    E Vreugdenhil

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  1. C P Fitzsimons
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Fitzsimons, C., van Hooijdonk, L., Schouten, M. et al. Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior. Mol Psychiatry 18, 993–1005 (2013). https://doi.org/10.1038/mp.2012.123

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