Regulation of Excitatory Synapses by Stress Hormones

  • Marian Joëls
  • Harm Krugers
  • Henk Karst


Shortly after stress, brain levels of many transmitters and hormones such as corticosterone are elevated. In the brain, corticosterone affects those cells that express high-affinity mineralocorticoid receptors (MRs) and/or lower-affinity glucocorticoid receptors (GRs). Principal neurons in the hippocampal cornus ammoni 1 (CA1) area and dentate gyrus abundantly express both MR and GR, while principal cells in the basolateral amygdala have high GR but relatively low MR levels. Neurons in all three areas quickly respond to corticosterone with an enhancement in spontaneous glutamatergic transmission, an effect that is nongenomic and involves MR. This rapid effect is transient in hippocampal cells but sustained in amygdala neurons. The areas differ in their slow gene-mediated response to corticosterone. Hippocampal CA1 cells show an increased current amplitude in response to spontaneously released glutamate-containing vesicles; synaptically evoked responses are generally unaffected. The number of action potentials during a period of depolarization is attenuated, via a slow GR-dependent pathway. By contrast, basolateral amygdala neurons show higher excitability and more efficient transfer of action potentials several hours after corticosteroid exposure. The dichotomy between the two areas could explain why emotional aspects of stressful events are generally better retained than neutral aspects.


Corticosterone Hippocampus Basolateral amygdala Stress Glucocorticoid receptor Mineralocorticoid receptor Nongenomic Glutamate Electrophysiology Hippocampus Basolateral amygdala 





α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid


Basolateral amygdala


Bovine serum albumin


Cornus ammoni 1


(Miniature) Excitatory postsynaptic current/potential


Extracellular signal-regulated kinase


Glucocorticoid receptor


Long-term depression


Long-term potentiation


Mitogen-activated protein kinase kinase


Mineralocorticoid receptor




  1. Abercrombie HC, Kalin NH, Thurow ME, Rosenkranz MA, Davidson RJ. Cortisol variation in humans affects memory for emotionally laden and neutral information. Behav Neurosci. 2003;117:505–16.PubMedCrossRefGoogle Scholar
  2. Avital A, Segal M, Richter-Levin G. Contrasting roles of corticosteroid receptors in hippocampal plasticity. J Neurosci. 2006;26:9130–4.PubMedCrossRefGoogle Scholar
  3. Beck SG, List TJ, Choi KC. Long- and short-term administration of corticosterone alters CA1 hippocampal neuronal properties. Neuroendocrinology. 1994;60:261–72.PubMedCrossRefGoogle Scholar
  4. Biddie SC, Hager GL. Glucocorticoid receptor dynamics and gene regulation. Stress. 2009;12:193–205.PubMedCrossRefGoogle Scholar
  5. Blank T, Nijholt I, Eckart K, Spiess J. Priming of long-term potentiation in mouse hippocampus by corticotropin-releasing factor and acute stress: implications for hippocampus-dependent learning. J Neurosci. 2002;22:3788–94.PubMedGoogle Scholar
  6. Bramham CR, Southard T, Ahlers ST, Sarvey JM. Acute cold stress leading to elevated corticosterone neither enhances synaptic efficacy nor impairs LTP in the dentate gyrus of freely moving rats. Brain Res. 1998;789:245–55.PubMedCrossRefGoogle Scholar
  7. Buchanan TW, Lovallo WR. Enhanced memory for emotional material following stress-level cortisol treatment in humans. Psychoneuroendocrinology. 2001;26:307–17.PubMedCrossRefGoogle Scholar
  8. Chameau P, Qin Y, Spijker S, Smit AB, Joëls M. Glucocorticoids specifically enhance L-type calcium current amplitude and affect calcium channel subunit expression in the mouse hippocampus. J Neurophysiol. 2007;97:5–14.PubMedCrossRefGoogle Scholar
  9. Chen CC, Yang CH, Huang CC, Hsu KS. Acute stress impairs hippocampal mossy fiber-CA3 long-term potentiation by enhancing cAMP-specific phosphodiesterase 4 activity. Neuropsychopharmacology. 2010;35:1605–17.PubMedCentralPubMedCrossRefGoogle Scholar
  10. Croce A, Astier H, Récasens M, Vignes M. Opposite effects of alpha 1- and beta-adrenoceptor stimulation on both glutamate- and gamma-aminobutyric acid-mediated spontaneous transmission in cultured rat hippocampal neurons. J Neurosci Res. 2003;71:516–25.PubMedCrossRefGoogle Scholar
  11. Datson NA, Morsink MC, Meijer OC, de Kloet ER. Central corticosteroid actions: search for gene targets. Eur J Pharmacol. 2008;583:272–89.PubMedCrossRefGoogle Scholar
  12. De Kloet ER, Joels M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci. 2005;6:463–75.PubMedCrossRefGoogle Scholar
  13. Di S, Malcher-Lopes R, Halmos KC, Tasker JG. Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J Neurosci. 2003;23:4850–7.PubMedGoogle Scholar
  14. Di S, Malcher-Lopes R, Marcheselli VL, Bazan NG, Tasker JG. Rapid glucocorticoid-mediated endocannabinoid release and opposing regulation of glutamate and gamma-aminobutyric acid inputs to hypothalamic magnocellular neurons. Endocrinology. 2005;146:4292–301.PubMedCrossRefGoogle Scholar
  15. Duvarci S, Pare D. Glucocorticoids enhance the excitability of principal basolateral amygdala neurons. J Neurosci. 2007;27:4482–91.PubMedCrossRefGoogle Scholar
  16. Evans RM, Arriza JL. A molecular framework for the actions of glucocorticoid hormones in the nervous system. Neuron. 1989;2:1105–12.PubMedCrossRefGoogle Scholar
  17. Funder JW. Minireview: Aldosterone and mineralocorticoid receptors: past, present, and future. Endocrinology. 2010;151:5098–102.PubMedCrossRefGoogle Scholar
  18. Gereau RW 4th, Conn PJ. Presynaptic enhancement of excitatory synaptic transmission by beta-adrenergic receptor activation. J Neurophysiol 1994;72:1438–42.PubMedGoogle Scholar
  19. Groc L, Choquet D, Chaouloff F. The stress hormone corticosterone conditions AMPAR surface trafficking and synaptic potentiation. Nat Neurosci. 2008;11:868–70.PubMedCrossRefGoogle Scholar
  20. Gutièrrez-Mecinas M, Trollope AF, Collins A, Morfett H, Hesketh SA, Kersanté F, Reul JM. Long-lasting behavioral responses to stress involve a direct interaction of glucocorticoid receptors with ERK1/2-MSK1-Elk-1 signaling. Proc Natl Acad Sci U S A. 2011;108:13806–11.PubMedCentralPubMedCrossRefGoogle Scholar
  21. Hilfiker S, Schweizer FE, Kao HT, Czernik AJ, Greengard P, Augustine GJ. Two sites of action for synapsin domain E in regulating neurotransmitter release. Nat Neurosci. 1998;1(2):9–35.Google Scholar
  22. Hirata R, Togashi H, Matsumoto M, Yamaguchi T, Izumi T, Yoshioka M. Characterization of stress-induced suppression of long-term potentiation in the hippocampal CA1 field of freely moving rats. Brain Res. 2008;1226:27–32.PubMedCrossRefGoogle Scholar
  23. Hu W, Zhang M, Czeh B, Flugge G, Zhang W. Stress impairs GABAergic network function in the hippocampus by activating nongenomic glucocorticoid receptors and affecting the integrity of the parvalbumin-expressing neuronal network. Neuropsychopharmacology. 2010;35:1693–707.PubMedCentralPubMedGoogle Scholar
  24. Hunter RG, Murakami G, Dewell S, Seligsohn M, Baker ME, Datson NA, McEwen BS, Pfaff DW. Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response. Proc Natl Acad Sci U S A. 2012;109:17657–62.PubMedCentralPubMedCrossRefGoogle Scholar
  25. Joels M, de Kloet ER. Effects of glucocorticoids and norepinephrine on the excitability in the hippocampus. Science. 1989;245:1502–5.PubMedCrossRefGoogle Scholar
  26. Joels M, de Kloet ER. Corticosteroid actions on amino acid-mediated transmission in rat CA1 hippocampal cells. J Neurosci. 1993;13:4082–90.PubMedGoogle Scholar
  27. Joels M, Velzing E, Nair S, Verkuyl JM, Karst H. Acute stress increases calcium current amplitude in rat hippocampus: temporal changes in physiology and gene expression. Eur J Neurosci. 2003;18:1315–24.PubMedCrossRefGoogle Scholar
  28. Joëls M, Sarabdjitsingh RA, Karst H. Unraveling the time domains of corticosteroid hormone influences on brain activity: rapid, slow, and chronic modes. Pharmacol Rev. 2012;64:901–38.PubMedCrossRefGoogle Scholar
  29. Karst H, Joels M. Corticosterone slowly enhances miniature excitatory postsynaptic current amplitude in mice CA1 hippocampal cells. J Neurophysiol. 2005;94:3479–86.PubMedCrossRefGoogle Scholar
  30. Karst H, Wadman WJ, Joëls M. Corticosteroid receptor-dependent modulation of calcium currents in rat hippocampal CA1 neurons. Brain Res. 1994;649:234–42.PubMedCrossRefGoogle Scholar
  31. Karst H, Karten YJ, Reichardt HM, de Kloet ER, Schutz G, Joels M. Corticosteroid actions in hippocampus require DNA binding of glucocorticoid receptor homodimers. Nat Neurosci. 2000;3:977–8.PubMedCrossRefGoogle Scholar
  32. Karst H, Nair S, Velzing E, Rumpff-van Essen L, Slagter E, Shinnick-Gallagher P, Joels M. Glucocorticoids alter calcium conductances and calcium channel subunit expression in basolateral amygdala neurons. Eur J Neurosci. 2002;16:1083–9.PubMedCrossRefGoogle Scholar
  33. Karst H, Berger S, Turiault M, Tronche F, Schutz G, Joels M. Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. Proc Natl Acad Sci U S A. 2005;102:19204–7.PubMedCentralPubMedCrossRefGoogle Scholar
  34. Karst H, Berger S, Erdmann G, Schutz G, Joels M. Metaplasticity of amygdalar responses to the stress hormone corticosterone. Proc Natl Acad Sci U S A. 2010;107:14449–54.PubMedCentralPubMedCrossRefGoogle Scholar
  35. Kavushansky A, Richter-Levin G. Effects of stress and corticosterone on activity and plasticity in the amygdala. J Neurosci Res. 2006;84:1580–7.PubMedCrossRefGoogle Scholar
  36. Kavushansky A, Vouimba RM, Cohen H, Richter-Levin G. Activity and plasticity in the CA1, the dentate gyrus, and the amygdala following controllable vs. uncontrollable water stress. Hippocampus. 2006;16:35–42.PubMedCrossRefGoogle Scholar
  37. Kerr DS, Campbell LW, Hao SY, Landfield PW. Corticosteroid modulation of hippocampal potentials: increased effect with aging. Science. 1989;245:1505–9.PubMedCrossRefGoogle Scholar
  38. Kerr DS, Campbell LW, Thibault O, Landfield PW. Hippocampal glucocorticoid receptor activation enhances voltage-dependent Ca2 + conductances: relevance to brain aging. Proc Natl Acad Sci U S A. 1992;89:8527–31.PubMedCentralPubMedCrossRefGoogle Scholar
  39. Kim JJ, Diamond DM. The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci. 2002;3:453–62.PubMedGoogle Scholar
  40. Kim JJ, Lee HJ, Welday AC, Song E, Cho J, Sharp PE, Jung MW, Blair HT. Stress-induced alterations in hippocampal plasticity, place cells, and spatial memory. Proc Natl Acad Sci U S A. 2007;104:18297–302.PubMedCentralPubMedCrossRefGoogle Scholar
  41. Kuhlmann S, Wolf OT. Arousal and cortisol interact in modulating memory consolidation in healthy young men. Behav Neurosci. 2006;120:217–23.PubMedCrossRefGoogle Scholar
  42. Liebmann L, Karst H, Sidiropoulou K, van Gemert N, Meijer OC, Poirazi P, Joels M. Differential effects of corticosterone on the slow afterhyperpolarization in the basolateral amygdala and CA1 region: possible role of calcium channel subunits. J Neurophysiol. 2008;99:958–68.PubMedCrossRefGoogle Scholar
  43. Liebmann L, Karst H, Joels M. Effects of corticosterone and the beta-agonist isoproterenol on glutamate receptor-mediated synaptic currents in the rat basolateral amygdala. Eur J Neurosci. 2009;30:800–7.PubMedCrossRefGoogle Scholar
  44. Lightman SL, Conway-Campbell BL. The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration. Nat Rev Neurosci. 2010;11:710–8.PubMedCrossRefGoogle Scholar
  45. Liu L, Wang C, Ni X, Sun J. A rapid inhibition of NMDA receptor current by corticosterone in cultured hippocampal neurons. Neurosci Lett. 2007;420:245–50.PubMedCrossRefGoogle Scholar
  46. Maggio N, Segal M. Differential corticosteroid modulation of inhibitory synaptic currents in the dorsal and ventral hippocampus. J Neurosci. 2009;29:2857–66.PubMedCrossRefGoogle Scholar
  47. Martin S, Henley JM, Holman D, Zhou M, Wiegert O, van Spronsen M, Joels M, Hoogenraad CC, Krugers HJ. Corticosterone alters AMPAR mobility and facilitates bidirectional synaptic plasticity. PLoS ONE. 2009;4:e4714.PubMedCentralPubMedCrossRefGoogle Scholar
  48. McIntyre CK, McGaugh JL, Williams CL. Interacting brain systems modulate memory consolidation. Neurosci Biobehav Rev. 2012;36:1750–62.PubMedCentralPubMedCrossRefGoogle Scholar
  49. Olijslagers JE, de Kloet ER, Elgersma Y, van Woerden GM, Joels M, Karst H. Rapid changes in hippocampal CA1 pyramidal cell function via pre- as well as postsynaptic membrane mineralocorticoid receptors. Eur J Neurosci. 2008;27:2542–50.PubMedCrossRefGoogle Scholar
  50. Orchinik M, Murray TF, Moore FL. A corticosteroid receptor in neuronal membranes. Science. 1991;252:1848–51.PubMedCrossRefGoogle Scholar
  51. Parfitt KD, Hoffer BJ, Browning MD. Norepinephrine and isoproterenol increase the phosphorylation of synapsin I and synapsin II in dentate slices of young but not aged Fisher 344 rats. Proc Natl Acad Sci U S A. 1991;88:2361–5.PubMedCentralPubMedCrossRefGoogle Scholar
  52. Pasricha N, Joels M, Karst H. Rapid effects of corticosterone in the mouse dentate gyrus via a nongenomic pathway. J Neuroendocrinol. 2011;23:143–7.PubMedCrossRefGoogle Scholar
  53. Passecker J, Hok V, Della-Chiesa A, Chah E, O’Mara SM. Dissociation of dorsal hippocampal regional activation under the influence of stress in freely behaving rats. Front Behav Neurosci. 2011;5:66.PubMedCentralPubMedCrossRefGoogle Scholar
  54. Pavlides C, Ogawa S, Kimura A, McEwen BS. Role of adrenal steroid mineralocorticoid and glucocorticoid receptors in long-term potentiation in the CA1 field of hippocampal slices. Brain Res. 1996;738:229–35.PubMedCrossRefGoogle Scholar
  55. Pfaff DW, Silva MT, Weiss JM. Telemetered recording of hormone effects on hippocampal neurons. Science. 1971;172:394–5.PubMedCrossRefGoogle Scholar
  56. Pu Z, Krugers HJ, Joels M. Corticosterone time-dependently modulates beta-adrenergic effects on long-term potentiation in the hippocampal dentate gyrus. Learn Mem. 2007;14:359–67.PubMedCentralPubMedCrossRefGoogle Scholar
  57. Pu Z, Krugers HJ, Joels M. Beta-adrenergic facilitation of synaptic plasticity in the rat basolateral amygdala in vitro is gradually reversed by corticosterone. Learn Mem. 2009;16:155–60.PubMedCrossRefGoogle Scholar
  58. Qiu S, Champagne DL, Peters M, Catania EH, Weeber EJ, Levitt P, Pimenta AF. Loss of limbic system-associated membrane protein leads to reduced hippocampal mineralocorticoid receptor expression, impaired synaptic plasticity, and spatial memory deficit. Biol Psychiatry. 2010;68:197–204.PubMedCentralPubMedCrossRefGoogle Scholar
  59. Reul JM, de Kloet ER. Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology. 1985;117:2505–11.PubMedCrossRefGoogle Scholar
  60. Reul JM, Hesketh SA, Collins A, Mecinas MG. Epigenetic mechanisms in the dentate gyrus act as a molecular switch in hippocampus-associated memory formation. Epigenetics. 2009;4:434–9.PubMedCrossRefGoogle Scholar
  61. Revest JM, Kaouane N, Mondin M, Le Roux A, Rougé-Pont F, Vallée M, Barik J, Tronche F, Desmedt A, Piazza PV. The enhancement of stress-related memory by glucocorticoids depends on synapsin-Ia/Ib. Mol Psychiatry. 2010;15:1140–51.PubMedCentralCrossRefGoogle Scholar
  62. Rey M, Carlier E, Soumireu-Mourat B. Effects of corticosterone on hippocampal slice electrophysiology in normal and adrenalectomized BALB/c mice. Neuroendocrinology. 1987;46:424–9.PubMedCrossRefGoogle Scholar
  63. Rimmele U, Domes G, Mathiak K, Hautzinger M. Cortisol has different effects on human memory for emotional and neutral stimuli. Neuroreport. 2003;14:2485–8.PubMedCrossRefGoogle Scholar
  64. Rodriguez Manzanares PA, Isoardi NA, Carrer HF, Molina VA. Previous stress facilitates fear memory, attenuates GABAergic inhibition, and increases synaptic plasticity in the rat basolateral amygdala. J Neurosci. 2005;25:8725–34.PubMedCrossRefGoogle Scholar
  65. Roozendaal B, Hernandez A, Cabrera SM, Hagewoud R, Malvaez M, Stefanko DP, Haettig J, Wood MA. Membrane-associated glucocorticoid activity is necessary for modulation of long-term memory via chromatin modification. J Neurosci. 2010;30:5037–46.PubMedCentralPubMedCrossRefGoogle Scholar
  66. Teschemacher A, Zeise ML, Zieglgansberger W. Corticosterone-induced decrease of inhibitory postsynaptic potentials in rat hippocampal pyramidal neurons in vitro depends on cytosolic factors. Neurosci Lett. 1996;215:83–6.PubMedCrossRefGoogle Scholar
  67. Tse YC, Bagot RC, Hutter JA, Wong AS, Wong TP. Modulation of synaptic plasticity by stress hormone associates with plastic alteration of synaptic NMDA receptor in the adult hippocampus. PLoS ONE. 2011;6:e27215.PubMedCentralPubMedCrossRefGoogle Scholar
  68. Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci. 2009;10:397–409.PubMedCrossRefGoogle Scholar
  69. Valentino RJ, Van Bockstaele E. Convergent regulation of locus coeruleus activity as an adaptive response to stress. Eur J Pharmacol. 2008;583:194–203.PubMedCentralPubMedCrossRefGoogle Scholar
  70. Van Gemert NG, Carvalho DM, Karst H, van der Laan S, Zhang M, Meijer OC, Hell JW, Joels M. Dissociation between rat hippocampal CA1 and dentate gyrus cells in their response to corticosterone: effects on calcium channel protein and current. Endocrinology. 2009;150:4615–24.PubMedCentralPubMedCrossRefGoogle Scholar
  71. Van Stegeren AH, Roozendaal B, Kindt M, Wolf OT, Joëls M. Interacting noradrenergic and corticosteroid systems shift human brain activation patterns during encoding. Neurobiol Learn Mem. 2010;93:56–65.PubMedCrossRefGoogle Scholar
  72. Vidal C, Jordan W, Zieglgansberger W. Corticosterone reduces the excitability of hippocampal pyramidal cells in vitro. Brain Res. 1986;383:54–9.PubMedCrossRefGoogle Scholar
  73. Weinberger C, Hollenberg SM, Ong ES, Harmon JM, Brower ST, Cidlowski J, Thompson EB, Rosenfeld MG, Evans RM. Identification of human glucocorticoid receptor complementary DNA clones by epitope selection. Science. 1985;228:740–2.PubMedCrossRefGoogle Scholar
  74. Whitlock JR, Heynen AJ, Shuler MG, Bear MF. Learning induces long-term potentiation in the hippocampus. Science. 2006;313:1093–7.PubMedCrossRefGoogle Scholar
  75. Wiegert O, Joels M, Krugers H. Timing is essential for rapid effects of corticosterone on synaptic potentiation in the mouse hippocampus. Learn Mem. 2006;13:110–3.PubMedCrossRefGoogle Scholar
  76. Wyrwoll CS, Holmes MC, Seckl JR. 11beta-hydroxysteroid dehydrogenases and the brain: from zero to hero, a decade of progress. Front Neuroendocrinol. 2011;32:265–86.PubMedCentralPubMedCrossRefGoogle Scholar
  77. Yamada K, McEwen BS, Pavlides C. Site and time dependent effects of acute stress on hippocampal long-term potentiation in freely behaving rats. Exp Brain Res. 2003;152:52–9.PubMedCrossRefGoogle Scholar
  78. Zeise ML, Teschemacher A, Arriagada J, Zieglgansberger W. Corticosterone reduces synaptic inhibition in rat hippocampal and neocortical neurons in vitro. J Neuroendocrinol. 1992;4:107–12.PubMedCrossRefGoogle Scholar
  79. Zhang Y, Sheng H, Qi J, Ma B, Sun J, Li S, Ni X. Glucocorticoid acts on a putative G-protein coupled receptor to rapidly regulate the activity of NMDA receptors in hippocampal neurons. Am J Physiol Endocrinol Metab. 2012;302:E747–58.PubMedCrossRefGoogle Scholar
  80. Zhou J, Zhang F, Zhang Y. Corticosterone inhibits generation of long-term potentiation in rat hippocampal slice: involvement of brain-derived neurotrophic factor. Brain Res. 2000;885:182–91.PubMedCrossRefGoogle Scholar
  81. Zhou M, Hoogenraad CC, Joëls M, Krugers HJ. Combined β-adrenergic and corticosteroid receptor activation regulates AMPA receptor function in hippocampal neurons. J Psychopharmacol. 2012;26:516–24.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Translational Neuroscience, Brain Center Rudolf MagnusUniversity Medical CenterUtrechtThe Netherlands
  2. 2.Swammerdam Institute for Life Sciences—Center for NeuroscienceUniversity of AmsterdamAmsterdamThe Netherlands

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