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Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory

Abstract

Corticosteroid stress hormones have a strong impact on the function of prefrontal cortex (PFC), a central region controlling cognition and emotion, though the underlying mechanisms are elusive. We found that behavioral stressor or short-term corticosterone treatment in vitro induces a delayed and sustained potentiation of the synaptic response and surface expression of N-methyl-D-aspartic acid receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in PFC pyramidal neurons through a mechanism depending on the induction of serum- and glucocorticoid-inducible kinase (SGK) and the activation of Rab4, which mediates receptor recycling between early endosomes and the plasma membrane. Working memory, a key function relying on glutamatergic transmission in PFC, is enhanced in acutely stressed animals through an SGK-dependent mechanism. These results suggest that acute stress, by activating glucocorticoid receptors, increases the trafficking and function of NMDARs and AMPARs through SGK/Rab4 signaling, which leads to the potentiated synaptic transmission, thereby facilitating cognitive processes mediated by the PFC.

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References

  1. McEwen BS . Protective and damaging effects of stress mediators. N Engl J Med 1998; 338: 171–179.

    Article  CAS  Google Scholar 

  2. McEwen BS . Stress and hippocampal plasticity. Annu Rev Neurosci 1999; 22: 105–122.

    Article  CAS  Google Scholar 

  3. McEwen BS . Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 2007; 87: 873–904.

    Article  Google Scholar 

  4. Funder JW . Glucocorticoid and mineralocorticoid receptors: biology and clinical relevance. Annu Rev Med 1997; 48: 231–240.

    Article  CAS  Google Scholar 

  5. Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC et al. Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo–pituitary–adrenocortical responsiveness. Front Neuroendocrinol 2003; 24: 151–180.

    Article  CAS  Google Scholar 

  6. de Kloet ER, Joëls M, Holsboer F . Stress and the brain: from adaptation to disease. Nat Rev Neurosci 2005; 6: 463–475.

    Article  CAS  Google Scholar 

  7. Joëls M . Corticosteroid effects in the brain: U-shape it. Trends Pharmacol Sci 2006; 27: 244–250.

    Article  Google Scholar 

  8. Lupien SJ, McEwen BS, Gunnar MR, Heim C . Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 2009; 10: 434–445.

    Article  CAS  Google Scholar 

  9. Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR et al. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci 2006; 26: 7870–7874.

    Article  CAS  Google Scholar 

  10. Cerqueira JJ, Mailliet F, Almeida OF, Jay TM, Sousa N . The prefrontal cortex as a key target of the maladaptive response to stress. J Neurosci 2007; 27: 2781–2787.

    Article  CAS  Google Scholar 

  11. Goldman-Rakic PS . Cellular basis of working memory. Neuron 1995; 14: 477–485.

    Article  CAS  Google Scholar 

  12. Yuen EY, Liu W, Karatsoreos IN, Feng J, McEwen BS, Yan Z . Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory. Proc Natl Acad Sci USA 2009; 106: 14075–14079.

    Article  CAS  Google Scholar 

  13. Webster MK, Goya L, Ge Y, Maiyar AC, Firestone GL . Characterization of SGK, a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum. Mol Cell Biol 1993; 13: 2031–2040.

    Article  CAS  Google Scholar 

  14. Zerial M, McBride H . Rab proteins as membrane organizers. Nat Rev Mol Cell Biol 2001; 2: 107–117.

    Article  CAS  Google Scholar 

  15. Yuen EY, Jiang Q, Chen P, Gu Z, Feng J, Yan Z . Serotonin 5-HT1A receptors regulate NMDA receptor channels through a microtubule-dependent mechanism. J Neurosci 2005; 25: 5488–5501.

    Article  CAS  Google Scholar 

  16. Karst H, Joëls M . Corticosterone slowly enhances miniature excitatory postsynaptic current amplitude in mice CA1 hippocampal cells. J Neurophysiol 2005; 94: 3479–3486.

    Article  CAS  Google Scholar 

  17. Groc L, Choquet D, Chaouloff F . The stress hormone corticosterone conditions AMPAR surface trafficking and synaptic potentiation. Nat Neurosci 2008; 11: 868–870.

    Article  CAS  Google Scholar 

  18. Malinow R, Malenka RC . AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci 2002; 25: 103–126.

    Article  CAS  Google Scholar 

  19. Kielland A, Bochorishvili G, Corson J, Zhang L, Rosin DL, Heggelund P et al. Activity patterns govern synapse-specific AMPA receptor trafficking between deliverable and synaptic pools. Neuron 2009; 62: 84–101.

    Article  CAS  Google Scholar 

  20. Kobayashi T, Cohen P . Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem J 1999; 339: 319–328.

    Article  CAS  Google Scholar 

  21. Lang F, Cohen P . Regulation and physiological roles of serum- and glucocorticoid-induced protein kinase isoforms. Sci STKE 2001; 108: RE17.

    Google Scholar 

  22. Schwarze SR, Ho A, Vocero-Akbani A, Dowdy SF . In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 1999; 285: 1569–1572.

    Article  CAS  Google Scholar 

  23. Yang L, Dan HC, Sun M, Liu Q, Sun XM, Feldman RI et al. Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res 2004; 64: 4394–4399.

    Article  CAS  Google Scholar 

  24. Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R . Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 2002; 110: 443–455.

    Article  CAS  Google Scholar 

  25. Qin Y, Zhu Y, Baumgart JP, Stornetta RL, Seidenman K, Mack V et al. State-dependent Ras signaling and AMPA receptor trafficking. Genes Dev 2005; 19: 2000–2015.

    Article  CAS  Google Scholar 

  26. Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW et al. Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions. Science 2002; 298: 846–850.

    Article  CAS  Google Scholar 

  27. Liu XJ, Gingrich JR, Vargas-Caballero M, Dong YN, Sengar A, Beggs S et al. Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex. Nat Med 2008; 14: 1325–1332.

    Article  CAS  Google Scholar 

  28. Bucci C, Parton RG, Mather IH, Stunnenberg H, Simons K, Hoflack B et al. The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway. Cell 1992; 70: 715–728.

    Article  CAS  Google Scholar 

  29. van der Sluijs P, Hull M, Webster P, Mâle P, Goud B, Mellman I . The small GTP-binding protein rab4 controls an early sorting event on the endocytic pathway. Cell 1992; 70: 729–740.

    Article  CAS  Google Scholar 

  30. Sheff DR, Daro EA, Hull M, Mellman I . The receptor recycling pathway contains two distinct populations of early endosomes with different sorting functions. J Cell Biol 1999; 145: 123–139.

    Article  CAS  Google Scholar 

  31. Ullrich O, Reinsch S, Urbé S, Zerial M, Parton RG . Rab11 regulates recycling through the pericentriolar recycling endosome. J Cell Biol 1996; 135: 913–924.

    Article  CAS  Google Scholar 

  32. Vitale G, Rybin V, Christoforidis S, Thornqvist P, McCaffrey M, Stenmark H et al. Distinct Rab-binding domains mediate the interaction of Rabaptin-5 with GTP-bound Rab4 and Rab5. EMBO J 1998; 17: 1941–1951.

    Article  CAS  Google Scholar 

  33. Lisman JE, Fellous JM, Wang XJ . A role for NMDA-receptor channels in working memory. Nat Neurosci 1998; 1: 273–275.

    Article  CAS  Google Scholar 

  34. Larsen JK, Divac I . Selective ablations within the prefrontal cortex of the rat and performance of delayed alternation. Physiolog Psychol 1978; 6: 15–17.

    Article  Google Scholar 

  35. Joëls M . Functional actions of corticosteroids in the hippocampus. Eur J Pharmacol 2008; 583: 312–321.

    Article  Google Scholar 

  36. Diamond DM, Bennett MC, Fleshner M, Rose GM . Inverted-U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentiation. Hippocampus 1992; 2: 421–430.

    Article  CAS  Google Scholar 

  37. Xu L, Anwyl R, Rowan MJ . Behavioural stress facilitates the induction of long-term depression in the hippocampus. Nature 1997; 387: 497–500.

    Article  CAS  Google Scholar 

  38. Xu L, Holscher C, Anwyl R, Rowan MJ . Glucocorticoid receptor and protein/RNA synthesis-dependent mechanisms underlie the control of synaptic plasticity by stress. Proc Natl Acad Sci USA 1998; 95: 3204–3208.

    Article  CAS  Google Scholar 

  39. Karst H, Berger S, Turiault M, Tronche F, Schütz G, Joëls M . Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. Proc Natl Acad Sci USA 2005; 102: 19204–19207.

    Article  CAS  Google Scholar 

  40. Wiegert O, Joëls M, Krugers H . Timing is essential for rapid effects of corticosterone on synaptic potentiation in the mouse hippocampus. Learn Mem 2006; 13: 110–113.

    Article  CAS  Google Scholar 

  41. Kim JJ, Diamond DM . The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 2002; 3: 453–462.

    Article  CAS  Google Scholar 

  42. Otani S, Blond O, Desce JM, Crepel F . Dopamine facilitates long-term depression of glutamatergic transmission in rat prefrontal cortex. Neuroscience 1998; 85: 669–676.

    Article  CAS  Google Scholar 

  43. Zhong P, Liu W, Gu Z, Yan Z . Serotonin facilitates long-term depression induction in prefrontal cortex via p38 MAPK/Rab5-mediated enhancement of AMPA receptor internalization. J Physiol 2008; 586: 4465–4479.

    Article  CAS  Google Scholar 

  44. Beato M, Sánchez-Pacheco A . Interaction of steroid hormone receptors with the transcription initiation complex. Endocr Rev 1996; 17: 587–609.

    Article  CAS  Google Scholar 

  45. Firestone GL, Giampaolo JR, O’Keeffe BA . Stimulus-dependent regulation of serum and glucocorticoid inducible protein kinase (SGK) transcription, subcellular localization and enzymatic activity. Cell Physiol Biochem 2003; 13: 1–12.

    Article  CAS  Google Scholar 

  46. Lang F, Böhmer C, Palmada M, Seebohm G, Strutz-Seebohm N, Vallon V . (Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms. Physiol Rev 2006; 86: 1151–1178.

    Article  CAS  Google Scholar 

  47. Alvarez de la Rosa D, Zhang P, Náray-Fejes-Tóth A, Fejes-Tóth G, Canessa CM . The serum and glucocorticoid kinase sgk increases the abundance of epithelial sodium channels in the plasma membrane of Xenopus oocytes. J Biol Chem 1999; 274: 37834–37839.

    Article  CAS  Google Scholar 

  48. Embark HM, Setiawan I, Poppendieck S, van de Graaf SF, Boehmer C, Palmada M et al. Regulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase isoforms SGK1 and SGK3 expressed in Xenopus oocytes. Cell Physiol Biochem 2004; 14: 203–212.

    Article  CAS  Google Scholar 

  49. Strutz-Seebohm N, Seebohm G, Mack AF, Wagner HJ, Just L, Skutella T et al. Regulation of GluR1 abundance in murine hippocampal neurons by serum- and glucocorticoid-inducible kinase 3. J Physiol 2005; 565: 381–390.

    Article  CAS  Google Scholar 

  50. Seebohm G, Strutz-Seebohm N, Birkin R, Dell G, Bucci C, Spinosa MR et al. Regulation of endocytic recycling of KCNQ1/KCNE1 potassium channels. Circ Res 2007; 100: 686–692.

    Article  CAS  Google Scholar 

  51. Wenthold RJ, Prybylowski K, Standley S, Sans N, Petralia RS . Trafficking of NMDA receptors. Annu Rev Pharmacol Toxicol 2003; 43: 335–358.

    Article  CAS  Google Scholar 

  52. Pfeffer SR . Rab GTPases: specifying and deciphering organelle identity and function. Trends Cell Biol 2001; 11: 487–491.

    Article  CAS  Google Scholar 

  53. Brown TC, Tran IC, Backos DS, Esteban JA . NMDA receptor-dependent activation of the small GTPase Rab5 drives the removal of synaptic AMPA receptors during hippocampal LTD. Neuron 2005; 45: 81–94.

    Article  CAS  Google Scholar 

  54. Park M, Penick EC, Edwards JG, Kauer JA, Ehlers MD . Recycling endosomes supply AMPA receptors for LTP. Science 2004; 305: 1972–1975.

    Article  CAS  Google Scholar 

  55. Chen P, Gu Z, Liu W, Yan Z . Glycogen synthase kinase 3 regulates NMDA receptor channel trafficking and function in cortical neurons. Mol Pharmacol 2007; 72: 40–51.

    Article  CAS  Google Scholar 

  56. Shors TJ . Stressful experience and learning across the lifespan. Annu Rev Psychol 2006; 57: 55–85.

    Article  Google Scholar 

  57. Shors TJ, Weiss C, Thompson RF . Stress-induced facilitation of classical conditioning. Science 1992; 257: 537–539.

    Article  CAS  Google Scholar 

  58. Joëls M, Pu Z, Wiegert O, Oitzl MS, Krugers HJ . Learning under stress: how does it work? Trends Cogn Sci 2006; 10: 152–158.

    Article  Google Scholar 

  59. Beylin AV, Shors TJ . Glucocorticoids are necessary for enhancing the acquisition of associative memories after acute stressful experience. Horm Behav 2003; 43: 124–131.

    Article  CAS  Google Scholar 

  60. Arnsten AF . Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci 2009; 10: 410–422.

    Article  CAS  Google Scholar 

  61. Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AF . Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci 2007; 10: 376–384.

    Article  CAS  Google Scholar 

  62. Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A et al. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 2007; 129: 397–410.

    Article  CAS  Google Scholar 

  63. Hains AB, Arnsten AF . Molecular mechanisms of stress-induced prefrontal cortical impairment: implications for mental illness. Learn Mem 2008; 15: 551–564.

    Article  Google Scholar 

  64. Kaufer D, Ogle WO, Pincus ZS, Clark KL, Nicholas AC, Dinkel KM et al. Restructuring the neuronal stress response with anti-glucocorticoid gene Delivery. Nat Neurosci 2004; 7: 947–953.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr Rob Malenka (Stanford University) for helpful comments on the article. We also thank Xiaoqing Chen and Dr Derek Daniels (Department of Psychology, SUNY at Buffalo) for excellent technical support. This work was supported by NIH grants to ZY.

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Yuen, E., Liu, W., Karatsoreos, I. et al. Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory. Mol Psychiatry 16, 156–170 (2011). https://doi.org/10.1038/mp.2010.50

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