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Dynamic molecular and anatomical changes in the glucocorticoid receptor in human cortical development

Molecular Psychiatry volume 16, pages 504–515 (2011)Cite this article

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Abstract

The glucocorticoid receptor (GR) has a critical role in determining the brain's capacity to respond to stress, and has been implicated in the pathogenesis of psychiatric illness. We hypothesized that key changes in cortical GR occur during adolescence and young adulthood, at a time when individuals are at increased risk of developing schizophrenia, bipolar disorder and major depression. We investigated the mRNA and protein expression of GR in the dorsolateral prefrontal cortex across seven developmental time points from infancy to adulthood. GR mRNA expression, determined by microarray and quantitative real-time PCR, was lowest in neonates and peaked around young adulthood. Western blotting revealed two dynamic patterns of GRα protein expression across the lifespan, with N-terminal variants displaying differing unique patterns of abundance. GRα-A and a 67-kDa GRα isoform mirrored mRNA trends and peaked in toddlers and late in adolescence, whereas a 40-kDa isoform, very likely a GRα-D variant, peaked in neonates and decreased across the lifespan. GRα protein was localized to pyramidal neurons throughout life and most strikingly in young adulthood, but to white matter astrocytes only in neonates and infants (<130 days). These results suggest that the neonatal and late adolescent periods represent critical windows of stress pathway development, and highlight the importance of white matter astrocytes and pyramidal neurons, respectively, at these stages of cortical development. Evidence of dynamic patterns of GR isoform expression and cellular localization across development strengthens the hypothesis that windows of vulnerability to stress exist across human cortical development.

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Acknowledgements

This study was supported by the Schizophrenia Research Institute, New South Wales Health, Macquarie Group Foundation, Prince of Wales Medical Research Institute and the University of New South Wales. Grant support was also received from the Stanley Medical Research Institute. We thank Heng Giap Woon, Alice Rothwell and Shan Yuan Tsai for technical assistance. DS was supported by an Australian Postgraduate Award.

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Authors and Affiliations

  1. Schizophrenia Research Institute, Sydney, NSW, Australia

    D Sinclair, J Wong & C S Weickert

  2. Schizophrenia Research Laboratory, Prince of Wales Medical Research Institute, Randwick, NSW, Australia

    D Sinclair, J Wong & C S Weickert

  3. Faculty of Medicine, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia

    D Sinclair & C S Weickert

  4. Department of Psychiatry, Stanley Laboratory of Brain Research, Bethesda, MD, USA

    M J Webster

  5. Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia

    J Wong

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Correspondence to C S Weickert.

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Sinclair, D., Webster, M., Wong, J. et al. Dynamic molecular and anatomical changes in the glucocorticoid receptor in human cortical development. Mol Psychiatry 16, 504–515 (2011). https://doi.org/10.1038/mp.2010.28

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