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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References
Gross KL, Cidlowski JA . Tissue-specific glucocorticoid action: a family affair. Trends Endocrinol Metab 2008; 19: 331–339.
Meaney MJ, Sapolsky RM, McEwen BS . The development of the glucocorticoid receptor system in the rat limbic brain. I. Ontogeny and autoregulation. Dev Brain Res 1985; 18: 159–164.
De Kloet ER, Joëls M, Holsboer F . Stress and the brain: from adaptation to disease. Nat Rev Neurosci 2005; 6: 463–475.
Turner JD, Schote AB, Macedo JA, Pelascini LPL, Muller CP . Tissue specific glucocorticoid receptor expression, a role for alternative first exon usage? Biochem Pharmacol 2006; 72: 1529–1537.
Lupien SJ, Fiocco A, Wan N, Maheu F, Lord C, Schramek T et al. Stress hormones and human memory function across the lifespan. Psychoneuroendocrinology 2005; 30: 225–242.
Sousa AR, Lane SJ, Cidlowski JA, Staynov DZ, Lee TH . Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor beta-isoform. J Allergy Clin Immunol 2000; 105: 943–950.
Turner JD, Muller CP . Structure of the glucocorticoid receptor (NR3C1) gene 5′ untranslated region: Identification, and tissue distribution of multiple new human exon 1. J Mol Endocrinol 2005; 35: 283–292.
Presul E, Schmidt S, Kofler R, Helmberg A . Identification, tissue expression, and glucocorticoid responsiveness of alternative first exons of the human glucocorticoid receptor. J Mol Endocrinol 2007; 38: 79–90.
Lu NZ, Cidlowski JA . Translational regulatory mechanisms generate N-terminal glucocorticoid receptor isoforms with unique transcriptional target genes. Mol Cell 2005; 18: 331–342.
Moalli PA, Pillay S, Krett NL, Rosen ST . Alternatively spliced glucocorticoid receptor messenger rnas in glucocorticoid-resistant human multiple myeloma cells. Cancer Res 1993; 53: 3877–3879.
Bamberger CM, Bamberger AM, de Castro M, Chrousos GP . Glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans. J Clin Invest 1995; 95: 2435–2441.
Rivers C, Levy A, Hancock J, Lightman S, Norman M . Insertion of an amino acid in the DNA-binding domain of the glucocorticoid receptor as a result of alternative splicing. J Clin Endocrinol Metab 1999; 84: 4283–4286.
Turner JD, Schote AB, Keipes M, Muller CP . A new transcript splice variant of the human glucocorticoid receptor: Identification and tissue distribution of hGRΔ313–338, an alternative exon 2 transactivation domain isoform. Ann NY Acad Sci 2007 pp 334–341.
Oakley RH, Webster JC, Jewell CM, Sar M, Cidlowski JA . Immunocytochemical analysis of the glucocorticoid receptor alpha isoform (GRalpha) using GRalpha-specific antibody. Steroids 1999; 64: 742–751.
Oakley RH, Webster JC, Sar M, Parker Jr CR, Cidlowski JA . Expression and subcellular distribution of the beta-isoform of the human glucocorticoid receptor. Endocrinology 1997; 138: 5028–5038.
Oakley RH, Sar M, Cidlowski JA . The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function. J Biol Chem 1996; 271: 9550–9559.
Pryce CR . Postnatal ontogeny of expression of the corticosteroid receptor genes in mammalian brains: inter-species and intra-species differences. Brain Res Rev 2008; 57: 596–605.
Hansson AC, Cintra A, Belluardo N, Sommer W, Bhatnagar M, Bader M et al. Gluco- and mineralocorticoid receptor-mediated regulation of neurotrophic factor gene expression in the dorsal hippocampus and the neocortex of the rat. Eur J Neurosci 2000; 12: 2918–2934.
Kumamaru E, Numakawa T, Adachi N, Yagasaki Y, Izumi A, Niyaz M et al. Glucocorticoid prevents brain-derived neurotrophic factor-mediated maturation of synaptic function in developing hippocampal neurons through reduction in the activity of mitogen-activated protein kinase. Mol Endocrinol 2008; 22: 546–558.
Schaaf MJ, de Jong J, de Kloet ER, Vreugdenhil E . Downregulation of BDNF mRNA and protein in the rat hippocampus by corticosterone. Brain Res 1998; 813: 112–120.
Weickert CS, Hyde TM, Lipska BK, Herman MM, Weinberger DR, Kleinman JE . Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry 2003; 8: 592–610.
Morsink MC, Steenbergen PJ, Vos JB, Karst H, Joels M, De Kloet ER et al. Acute activation of hippocampal glucocorticoid receptors results in different waves of gene expression throughout time. J Neuroendocrinol 2006; 18: 239–252.
Lewis DA, Gonzalez-Burgos G . Neuroplasticity of neocortical circuits in schizophrenia. Neuropsychopharmacology 2008; 33: 141–165.
Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci 2003; 23: 6315–6326.
Qiu HT, Meng HQ, Song C, Xiu MH, Chen DC, Zhu FY et al. Association between monoamine oxidase (MAO)-A gene variants and schizophrenia in a Chinese population. Brain Res 2009; 1287: 67–73.
Deckert J, Catalano M, Syagailo YV, Bosi M, Okladnova O, Di Bella D et al. Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum Mol Genet 1999; 8: 621–624.
Datson NA, van der Perk J, de Kloet ER, Vreugdenhil E . Identification of corticosteroid-responsive genes in rat hippocampus using serial analysis of gene expression. Eur J Neurosci 2001; 14: 675–689.
Weickert CS, Webster MJ, Hyde TM, Herman MM, Bachus SE, Bali G et al. Reduced GAP-43 mRNA in dorsolateral prefrontal cortex of patients with schizophrenia. Cereb Cortex 2001; 11: 136–147.
Tian SY, Wang J-F, Bezchlibnyk YB, Young LT . Immunoreactivity of 43 kDa growth-associated protein is decreased in post mortem hippocampus of bipolar disorder and schizophrenia. Neurosci Lett 2007; 411: 123–127.
Law AJ, Pei Q, Walker M, Gordon-Andrews H, Weickert CS, Feldon J et al. Early parental deprivation in the marmoset monkey produces long-term changes in hippocampal expression of genes involved in synaptic plasticity and implicated in mood disorder. Neuropsychopharmacology 2008; 34: 1381–1394.
Chen B, Wang J-F, Sun X, Young LT . Regulation of GAP-43 expression by chronic desipramine treatment in rat cultured hippocampal cells. Biol Psychiatry 2003; 53: 530–537.
Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM . Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 2008; 3: 97–106.
McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonte B, Szyf M et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 2009.
Cannon M, Clarke MC . Risk for schizophrenia—broadening the concepts, pushing back the boundaries. Schizophrenia Res 2005; 79: 5–13.
Mück-Seler D, Pivac N, Jakovljevic M, Brzovic Z . Platelet serotonin, plasma cortisol, and dexamethasone suppression test in schizophrenic patients. Biol Psychiatry 1999; 45: 1433–1439.
Carroll BJ, Feinberg M, Greden JF, Tarika J, Albala AA, Haskett RF et al. A specific laboratory test for the diagnosis of melancholia. Standardization, validation, and clinical utility. Arch Gen Psychiatry 1981; 38: 15–22.
Poland RE, Rubin RT, Lesser IM, Lane LA, Hart PJ . Neuroendocrine aspects of primary endogenous depression. II. Serum dexamethasone concentrations and hypothalamic-pituitary-adrenal cortical activity as determinants of the dexamethasone suppression test response. Arch Gen Psychiatry 1987; 44: 790–795.
Van Cauter E, Linkowski P, Kerkhofs M, Hubain P, L’Hermite-Baleriaux M, Leclercq R et al. Circadian and sleep-related endocrine rhythms in schizophrenia. Arch Gen Psychiatry 1991; 48: 348–356.
Linkowski P, Kerkhofs M, Van Onderbergen A, Hubain P, Copinschi G, L’Hermite-Baleriaux M et al. The 24-hour profiles of cortisol, prolactin, and growth hormone secretion in mania. Arch Gen Psychiatry 1994; 51: 616–624.
Thakore JH, Mann JN, Vlahos I, Martin A, Reznek R . Increased visceral fat distribution in drug-naive and drug-free patients with schizophrenia. Inter J Obesity 2002; 26: 137–141.
Carroll, Curtis GC, Mendels J . Neuroendocrine regulation in depression. I. Limbic system-adrenocortical dysfunction. Arch Gen Psychiatry 1976; 33: 1039–1044.
Knable MB, Torrey EF, Webster MJ, Bartko JJ . Multivariate analysis of prefrontal cortical data from the Stanley Foundation Neuropathology Consortium. Brain Res Bull 2001; 55: 651–659.
Webster MJ, Knable MB, O’Grady J, Orthmann J, Weickert CS . Regional specificity of brain glucocorticoid receptor mRNA alterations in subjects with schizophrenia and mood disorders. Mol Psychiatry 2002; 7: 985–994.
Perlman WR, Webster MJ, Kleinman JE, Weickert CS . Reduced glucocorticoid and estrogen receptor alpha messenger ribonucleic acid levels in the amygdala of patients with major mental illness. Biol Psychiatry 2004; 56: 844–852.
DeRijk RH, van Leeuwen N, Klok MD, Zitman FG . Corticosteroid receptor-gene variants: modulators of the stress-response and implications for mental health. Eur J Pharmacol 2008; 585: 492–501.
Wust S, Van Rossum EFC, Federenko IS, Koper JW, Kumsta R, Hellhammer DH . Common polymorphisms in the glucocorticoid receptor gene are associated with adrenocortical responses to psychosocial stress. J Clin Endocrinol Metabol 2004; 89: 565–573.
Van West D, Van Den Eede F, Del-Favero J, Souery D, Norrback KF, Van Duijn C et al. Glucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression. Neuropsychopharmacology 2006; 31: 620–627.
Diorio D, Viau V, Meaney MJ . The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. J Neurosci 1993; 13: 3839–3847.
Cotter D, Pariante CM . Stress and the progression of the developmental hypothesis of schizophrenia. Br J Psychiatry 2002; 181: 363–365.
Sippell WG, Doerr HG, Bidlingmaier F, Knorr D . Plasma levels of aldosterone, corticosterone, 11-deoxycorticosterone, progesterone, 17-hydroxyprogesterone, cortisol, and cortisone during infancy and childhood. Pediatric Res 1980; 14: 39–46.
Larsson CA, Gullberg B, Rastam L, Lindblad U . Salivary cortisol differs with age and sex and shows inverse associations with WHR in Swedish women: a cross-sectional study. BMC Endocr Disord 2009; 9: 16.
Van Cauter E, Leproult R, Kupfer DJ . Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab 1996; 81: 2468–2473.
Gunnar MR, Wewerka S, Frenn K, Long JD, Griggs C . Developmental changes in hypothalamus-pituitary-adrenal activity over the transition to adolescence: normative changes and associations with puberty. Dev Psychopathol 2009; 21: 69–85.
Jansen J, Beijers R, Riksen-Walraven M, de Weerth C . Cortisol reactivity in young infants. Psychoneuroendocrinology (in press).
Otte C, Hart S, Neylan TC, Marmar CR, Yaffe K, Mohr DC . A meta-analysis of cortisol response to challenge in human aging: importance of gender. Psychoneuroendocrinology 2005; 30: 80–91.
Kudielka BM, Buske-Kirschbaum A, Hellhammer DH, Kirschbaum C . HPA axis responses to laboratory psychosocial stress in healthy elderly adults, younger adults, and children: impact of age and gender. Psychoneuroendocrinology 2004; 29: 83–98.
Tohgi H, Utsugisawa K, Yamagata M, Yoshimura M . Effects of age on messenger RNA expression of glucocorticoid, thyroid hormone, androgen, and estrogen receptors in postmortem human hippocampus. Brain Res 1995; 700: 245–253.
Bohn MC, Dean D, Hussain S, Giuliano R . Development of mRNAs for glucocorticoid and mineralocorticoid receptors in rat hippocampus. Brain Res Dev Brain Res 1994; 77: 157–162.
Peiffer A, Barden N, Meaney MJ . Age-related changes in glucocorticoid receptor binding and mRNA levels in the rat brain and pituitary. Neurobiol Aging 1991; 12: 475–479.
Galeeva A, Ordyan N, Pivina S, Pelto-Huikko M . Expression of glucocorticoid receptors in the hippocampal region of the rat brain during postnatal development. J Chem Neuroanat 2006; 31: 216–225.
Perlman WR, Webster MJ, Herman MM, Kleinman JE, Weickert CS . Age-related differences in glucocorticoid receptor mRNA levels in the human brain. Neurobiol Aging 2007; 28: 447–458.
Weickert CS, Elashoff M, Richards AB, Sinclair D, Bahn S, Paabo S et al. Transcriptome analysis of male-female differences in prefrontal cortical development. Mol Psychiatry 2009; 14: 558–561.
Wong J, Webster MJ, Cassano H, Weickert CS . Changes in alternative brain-derived neurotrophic factor transcript expression in the developing human prefrontal cortex. Eur J Neurosci 2009; 29: 1311–1322.
Montague D, Weickert CS, Tomaskovic-Crook E, Rothmond DA, Kleinman JE, Rubinow DR . Oestrogen receptor alpha localisation in the prefrontal cortex of three mammalian species. J Neuroendocrinol 2008; 20: 893–903.
Schnell SA, Staines WA, Wessendorf MW . Reduction of lipofuscin-like autofluorescence in fluorescently labeled tissue. J Histochem Cytochem 1999; 47: 719–730.
Psarra A-MG, Solakidi S, Trougakos IP, Margaritis LH, Spyrou G, Sekeris CE . Glucocorticoid receptor isoforms in human hepatocarcinoma HepG2 and SaOS-2 osteosarcoma cells: presence of glucocorticoid receptor alpha in mitochondria and of glucocorticoid receptor beta in nucleoli. Inter J Biochem Cell Biol 2005; 37: 2544–2558.
Moutsatsou P, Psarra AM, Tsiapara A, Paraskevakou H, Davaris P, Sekeris CE . Localization of the glucocorticoid receptor in rat brain mitochondria. Arch Biochem Biophys 2001; 386: 69–78.
Vanderbilt JN, Miesfeld R, Maler BA, Yamamoto KR . Intracellular receptor concentration limits glucocorticoid-dependent enhancer activity. Mol Endocrinol (Baltimore, MD) 1987; 1: 68–74.
Levine S . Primary social relationships influence the development of the hypothalamic—pituitary—adrenal axis in the rat. Physiol Behav 2001; 73: 255–260.
Champagne DL, de Kloet ER, Joels M . Fundamental aspects of the impact of glucocorticoids on the (immature) brain. Semin Fetal Neonatal Med 2009; 14: 136–142.
Cotter DR, Pariante CM, Everall IP . Glial cell abnormalities in major psychiatric disorders: the evidence and implications. Brain Res Bull 2001; 55: 585–595.
Webster MJ, O’Grady J, Kleinman JE, Weickert CS . Glial fibrillary acidic protein mRNA levels in the cingulate cortex of individuals with depression, bipolar disorder and schizophrenia. Neuroscience 2005; 133: 453–461.
Andersen SL . Trajectories of brain development: Point of vulnerability or window of opportunity? Neurosci Biobehav Rev 2003; 27: 3–18.
Andersen SL, Teicher MH . Stress, sensitive periods and maturational events in adolescent depression. Trends Neurosci 2008; 31: 183–191.
Andersen SL, Tomada A, Vincow ES, Valente E, Polcari A, Teicher MH . Preliminary evidence for sensitive periods in the effect of childhood sexual abuse on regional brain development. J Neuropsychiatry Clin Neurosci 2008; 20: 292–301.
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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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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DOI: https://doi.org/10.1038/mp.2010.28
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