Working Memory Performance Is Associated with Common Glucocorticoid Receptor Gene PolymorphismsKumsta R.a · Entringer S.a · Koper J.W.b · van Rossum E.F.C.b · Hellhammer D.H.a · Wüst S.a
aDepartment of Theoretical and Clinical Psychobiology, University of Trier, Trier, Germany; bDepartment of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
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Article / Publication Details
Cortisol has a modulatory influence on cognitive functions in humans. Both impairing and enhancing effects of cortisol administration have been shown for hippocampus-dependent declarative memory, and impairing effects have been shown for prefrontal-cortex-dependent working memory function. Given the high density of glucocorticoid (GC) receptors in the prefrontal cortex, we investigated whether common polymorphisms of the GC receptor (GR) gene (ER22/23EK, N363S, BclI, 9β A3669G) modulate the influence of cortisol administration on working memory. Working memory performance was investigated in 169 subjects on 10 mg hydrocortisone (cortisol) and placebo using an item recognition task. No impairing effect of hydrocortisone treatment became evident. However, a sex × genotype interaction on general working memory performance was revealed (p = 0.02). While female heterozygous carriers of the 9β G allele displayed faster reaction times than the other genotype groups, 9β G heterozygous men were relatively slower. Heritability estimates for memory are roughly 50%, indicating that common genetic polymorphisms have an important impact on cognitive performance. Our results suggest that variants of the GR gene might explain some of the variance attributable to genetic factors. Furthermore, it can be speculated that they modulate the individual vulnerability for memory impairments related to stress-related psychiatric disorders.
© 2009 S. Karger AG, Basel
- de Kloet ER, Oitzl MS, Joels M: Stress and cognition: are corticosteroids good or bad guys? Trends Neurosci 1999;22:422–426.
- Holsboer F: The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 2000;23:477–501.
- Castaneda AE, Tuulio-Henriksson A, Marttunen M, Suvisaari J, Lonnqvist J: A review on cognitive impairments in depressive and anxiety disorders with a focus on young adults. J Affect Disord 2008;106:1–27.
- Yehuda R: Post-traumatic stress disorder. N Engl J Med 2002;346:108–114.
- Belanoff JK, Gross K, Yager A, Schatzberg AF: Corticosteroids and cognition. J Psychiatr Res 2001;35:127–145.
- Gold PW, Drevets WC, Charney DS: New insights into the role of cortisol and the glucocorticoid receptor in severe depression. Biol Psychiatry 2002;52:381–385.
- Lupien S, Lecours AR, Lussier I, Schwartz G, Nair NP, Meaney MJ: Basal cortisol levels and cognitive deficits in human aging. J Neurosci 1994;14:2893–2903.
- Lupien S, Richter R, Risch SC, Mirow A, Gillin JC, Hauger RL: Time course of the corticosteroid-dopaminergic interaction during metyrapone and dexamethasone administration. Psychiatry Res 1995;58:23–35.
- McEwen BS, Sapolsky RM: Stress and cognitive function. Curr Opin Neurobiol 1995;5:205–216.
- Wolf OT: HPA axis and memory. Best Pract Res Clin Endocrinol Metab 2003;17:287–299.
- Kirschbaum C, Wolf OT, May M, Wippich W, Hellhammer DH: Stress- and treatment-induced elevations of cortisol levels associated with impaired declarative memory in healthy adults. Life Sci 1996;58:1475–1483.
- Lupien SJ, McEwen BS: The acute effects of corticosteroids on cognition: integration of animal and human model studies. Brain Res Brain Res Rev 1997;24:1–27.
- Lupien SJ, Wilkinson CW, Briere S, Menard C, Ng Ying Kin NM, Nair NP: The modulatory effects of corticosteroids on cognition: studies in young human populations. Psychoneuroendocrinology 2002;27:401–416.
- Roozendaal B: Stress and memory: opposing effects of glucocorticoids on memory consolidation and memory retrieval. Neurobiol Learn Mem 2002;78:578–595.
- Oitzl MS, Reichardt HM, Joels M, de Kloet ER: Point mutation in the mouse glucocorticoid receptor preventing DNA binding impairs spatial memory. Proc Natl Acad Sci USA 2001;98:12790–12795.
- Het S, Ramlow G, Wolf OT: A meta-analytic review of the effects of acute cortisol administration on human memory. Psychoneuroendocrinology 2005;30:771–784.
- McEwen BS, De Kloet ER, Rostene W: Adrenal steroid receptors and actions in the nervous system. Physiol Rev 1986;66:1121–1188.
- Sarrieau A, Dussaillant M, Sapolsky RM, Aitken DH, Olivier A, Lal S, Rostene WH, Quirion R, Meaney MJ: Glucocorticoid binding sites in human temporal cortex. Brain Res 1988;442:157–160.
- Diamond A: Abilities and neural mechanisms underlying AB performance. Child Dev 1988;59:523–527.
- Dolan RJ, Fletcher PC: Dissociating prefrontal and hippocampal function in episodic memory encoding. Nature 1997;388:582–585.
Fuster JM: The Prefrontal Cortex: Anatomy, Physiology and Neuropsychology of the Frontal Lobe. New York, Raven Press, 1989.
- Smith EE, Jonides J, Marshuetz C, Koeppe RA: Components of verbal working memory: evidence from neuroimaging. Proc Natl Acad Sci USA 1998;95:876–882.
Baddeley A: Working Memory. New York, Oxford University Press, 1986.
- Lupien SJ, Gillin CJ, Hauger RL: Working memory is more sensitive than declarative memory to the acute effects of corticosteroids: a dose-response study in humans. Behav Neurosci 1999;113:420–430.
- Van Rossum EF, Lamberts SW: Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition. Recent Prog Horm Res 2004;59:333–357.
- Huizenga NA, Koper JW, De Lange P, Pols HA, Stolk RP, Burger H, Grobbee DE, Brinkmann AO, De Jong FH, Lamberts SW: A polymorphism in the glucocorticoid receptor gene may be associated with and increased sensitivity to glucocorticoids in vivo. J Clin Endocrinol Metab 1998;83:144–151.
- Koper JW, Stolk RP, de Lange P, Huizenga NA, Molijn GJ, Pols HA, Grobbee DE, Karl M, de Jong FH, Brinkmann AO, Lamberts SW: Lack of association between five polymorphisms in the human glucocorticoid receptor gene and glucocorticoid resistance. Hum Genet 1997;99:663–668.
- Russcher H, Smit P, van den Akker EL, van Rossum EF, Brinkmann AO, de Jong FH, Lamberts SW, Koper JW: Two polymorphisms in the glucocorticoid receptor gene directly affect glucocorticoid-regulated gene expression. J Clin Endocrinol Metab 2005;90:5804–5810.
- Derijk RH, Schaaf MJ, Turner G, Datson NA, Vreugdenhil E, Cidlowski J, de Kloet ER, Emery P, Sternberg EM, Detera-Wadleigh SD: A human glucocorticoid receptor gene variant that increases the stability of the glucocorticoid receptor beta-isoform mRNA is associated with rheumatoid arthritis. J Rheumatol 2001;28:2383–2388.
- van Rossum EF, Koper JW, Huizenga NA, Uitterlinden AG, Janssen JA, Brinkmann AO, Grobbee DE, de Jong FH, van Duyn CM, Pols HA, Lamberts SW: A polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels. Diabetes 2002;51:3128–3134.
- Weiss LA, Abney M, Cook EH Jr, Ober C: Sex-specific genetic architecture of whole blood serotonin levels. Am J Hum Genet 2005;76:33–41.
- Kurina LM, Weiss LA, Graves SW, Parry R, Williams GH, Abney M, Ober C: Sex differences in the genetic basis of morning serum cortisol levels: genome-wide screen identifies two novel loci specific to women. J Clin Endocrinol Metab 2005;90:4747–4752.
- Williams RB, Marchuk DA, Gadde KM, Barefoot JC, Grichnik K, Helms MJ, Kuhn CM, Lewis JG, Schanberg SM, Stafford-Smith M, Suarez EC, Clary GL, Svenson IK, Siegler IC: Serotonin-related gene polymorphisms and central nervous system serotonin function. Neuropsychopharmacology 2003;28:533–541.
- Jabbi M, Korf J, Kema IP, Hartman C, van der Pompe G, Minderaa RB, Ormel J, den Boer JA: Convergent genetic modulation of the endocrine stress response involves polymorphic variations of 5-HTT, COMT and MAOA. Mol Psychiatry 2007;12:483–490.
- Wüst S, Kumsta R, Treutlein J, Frank J, Entringer S, Schulze TG, Rietschel M: Sex-specific association between the 5-HTT gene-linked polymorphic region and basal cortisol secretion. Psychoneuroendocrinology 2009;34:972–982.
- Kumsta R, Entringer S, Koper JW, van Rossum EF, Hellhammer DH, Wust S: Sex specific associations between common glucocorticoid receptor gene variants and hypothalamus-pituitary-adrenal axis responses to psychosocial stress. Biol Psychiatry 2007;62:863–869.
- Sternberg S: High-speed scanning in human memory. Science 1966;153:652–654.
Costa P, McCrae R: Revised Neo Personality Inventory (Neo PI-R) and Neo Five Factor Inventory (Neo-FFI) Manual. Odessa, Psychological Assessment Resources, 1992.
- Miller SA, Dykes DD, Polesky HF: A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215.
- Dressendörfer RA, Kirschbaum C, Rohde W, Stahl F, Strasburger CJ: Synthesis of a cortisol-biotin conjugate and evaluation as a tracer in an immunoassay for salivary cortisol measurement. J Steroid Biochem Mol Biol 1992;43:683–692.
- van den Akker EL, Nouwen JL, Melles DC, Rossum EF, Koper JW, Uitterlinden AG, Hofman A, Verbrugh HA, Pols HA, Lamberts SW, van Belkum A: Staphylococcusaureus nasal carriage is associated with glucocorticoid receptor gene polymorphisms. J Infect Dis 2006;194:814–818.
- Weiss LA, Pan L, Abney M, Ober C: The sex-specific genetic architecture of quantitative traits in humans. Nat Genet 2006;38:218–222.
- Charmandari E, Chrousos GP, Ichijo T, Bhattacharyya N, Vottero A, Souvatzoglou E, Kino T: The human glucocorticoid receptor (HGR) beta isoform suppresses the transcriptional activity of HGRalpha by interfering with formation of active coactivator complexes. Mol Endocrinol 2005;19:52–64.
- Syed AA, Irving JA, Redfern CP, Hall AG, Unwin NC, White M, Bhopal RS, Weaver JU: Association of glucocorticoid receptor polymorphism A3669G in exon 9beta with reduced central adiposity in women. Obesity (Silver Spring) 2006;14:759–764.
- van den Akker EL, Koper JW, van Rossum EF, Dekker MJ, Russcher H, de Jong FH, Uitterlinden AG, Hofman A, Pols HA, Witteman JC, Lamberts SW: Glucocorticoid receptor gene and risk of cardiovascular disease. Arch Intern Med 2008;168:33–39.
- van den Akker EL, Russcher H, van Rossum EF, Brinkmann AO, de Jong FH, Hokken A, Pols HA, Koper JW, Lamberts SW: Glucocorticoid receptor polymorphism affects transrepression but not transactivation. J Clin Endocrinol Metab 2006;91:2800–2803.
- De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M: Brain corticosteroid receptor balance in health and disease. Endocr Rev 1998;19:269–301.
- McClearn GE, Johansson B, Berg S, Pedersen NL, Ahern F, Petrill SA, Plomin R: Substantial genetic influence on cognitive abilities in twins 80 or more years old. Science 1997;276:1560–1563.
- de Quervain DJ, Henke K, Aerni A, Coluccia D, Wollmer MA, Hock C, Nitsch RM, Papassotiropoulos A: A functional genetic variation of the 5-HT2a receptor affects human memory. Nat Neurosci 2003;6:1141–1142.
- Meyer-Lindenberg A, Nichols T, Callicott JH, Ding J, Kolachana B, Buckholtz J, Mattay VS, Egan M, Weinberger DR: Impact of complex genetic variation in COMT on human brain function. Mol Psychiatry 2006;11:867–877.
- Gatt JM, Clark CR, Kemp AH, Liddell BJ, Dobson-Stone C, Kuan SA, Schofield PR, Williams LM: A genotype-endophenotype-phenotype path model of depressed mood: integrating cognitive and emotional markers. J Integr Neurosci 2007;6:75–104.
- Rybakowski JK, Borkowska A, Czerski PM, Skibinska M, Hauser J: Polymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients. Bipolar Disord 2003;5:468–472.
Kumsta R, Moser D, Streit F, Koper JW, Wüst S: Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance. Am J Med Genet Part B 2008; DOI: 10.1002/ajmg.b30387.
- van West D, Van Den Eede F, Del-Favero J, Souery D, Norrback KF, Van Duijn C, Sluijs S, Adolfsson R, Mendlewicz J, Deboutte D, Van Broeckhoven C, Claes S: Glucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression. Neuropsychopharmacology 2006;31:620–627.
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