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The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission

Nature Reviews Neuroscience volume 13, pages 22–37 (2012)Cite this article

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Key Points

  • Excitatory synapses in the brain, which use glutamate as the primary neurotransmitter, represent a crucial target for the action of stress and its mediators. Mounting evidence suggests that stress, along with the associated hormonal and neurochemical mediators (particularly glucocorticoids), induces changes in glutamate release, transmission and metabolism in cortical and limbic brain areas, thereby influencing cognitive and emotional processing and behaviour.

  • Depending on age, gender, duration and the type of the stressors experienced, stress may either have beneficial effects on cognitive and emotional functions or induce noxious and maladaptive changes in brain tissue, which have been linked to the development of neuropsychiatric disorders.

  • Acute stress enhances glutamatergic synaptic transmission in the prefrontal cortex and other limbic regions, thereby facilitating certain cognitive functions.

  • Acute stress increases glutamate release, membrane trafficking of AMPA and NMDA receptors, and potentially glutamate clearance in the prefrontal cortex through various mechanisms that involve glucocorticoid regulation.

  • Chronic stress has been associated with a loss of glutamate receptors, impaired glutamate cycling and a suppression of glutamate transmission that may be attributable to the observed impairment of prefrontal cortex-dependent cognitive functions.

  • These findings suggest that a new line of drug development aimed at minimizing the effects of chronic stress exposure on the function of the glutamatergic neurotransmitter system may prove beneficial in clinical settings. Straightforward pharmacological intervention on different regulatory sites of the glutamate synapse is a possible strategy for bypassing the unmet therapeutic needs posed by traditional drugs based on monoaminergic mechanisms.

Abstract

Mounting evidence suggests that acute and chronic stress, especially the stress-induced release of glucocorticoids, induces changes in glutamate neurotransmission in the prefrontal cortex and the hippocampus, thereby influencing some aspects of cognitive processing. In addition, dysfunction of glutamatergic neurotransmission is increasingly considered to be a core feature of stress-related mental illnesses. Recent studies have shed light on the mechanisms by which stress and glucocorticoids affect glutamate transmission, including effects on glutamate release, glutamate receptors and glutamate clearance and metabolism. This new understanding provides insights into normal brain functioning, as well as the pathophysiology and potential new treatments of stress-related neuropsychiatric disorders.

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Figure 1: The tripartite glutamate synapse.
Figure 2: Acute stress rapidly enhances glutamate release in prefrontal and frontal cortex.
Figure 3: Stress induces changes in glutamate receptor trafficking and function in the prefrontal cortex.
Figure 4: Chronic stress affects glial cells and glutamate metabolism.
Figure 5: Pharmacological targets.

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References

  1. Selye, H. A syndrome produced by diverse nocuous agents. Nature 138, 32 (1936).

    Article  Google Scholar 

  2. Lazarus, R. S. & Folkman, S. Stress, Appraisal and Coping (Springer, New York, 1984).

    Google Scholar 

  3. McEwen, B. S. Protective and damaging effects of stress mediators. N. Engl. J. Med. 338, 171–179 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. McEwen, B. S. & Gianaros, P. J. Stress- and allostasis-induced brain plasticity. Annu. Rev. Med. 62, 431–445 (2011). A recent overview of plasticity of the brain based on animal model studies and human brain research. The overview is based on the conceptual model of allostasis and allostatic load (see reference 3), in which the brain is the central organ of stress and adaptation and regulates and responds to stress hormones and other stress mediators.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Liston, C. et al. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J. Neurosci. 26, 7870–7874 (2006). A key paper that showed reversible stress-induced plasticity of the PFC along with the resultant stress-induced behavioural deficits in an animal model. This paper led to a study in humans (reference 115) that showed stress-induced disruption of PFC processing and attentional control.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Vyas, A., Mitra, R., Shankaranarayana Rao, B. S. & Chattarji, S. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J. Neurosci. 22, 6810–6818 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. McEwen, B. S. Stress and hippocampal plasticity. Annu. Rev. Neurosci. 22, 105–122 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Lupien, S. J., McEwen, B. S., Gunnar, M. R. & Heim, C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nature Rev. Neurosci. 10, 434–445 (2009).

    Article  CAS  Google Scholar 

  9. Diamond, D. M., Campbell, A. M., Park, C. R., Halonen, J. & Zoladz, P. R. The temporal dynamics model of emotional memory processing: a synthesis on the neurobiological basis of stress-induced amnesia, flashbulb and traumatic memories, and the Yerkes-Dodson law. Neural Plast. 2007, 60803 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Arnsten, A. F. Stress signalling pathways that impair prefrontal cortex structure and function. Nature Rev. Neurosci. 10, 410–422 (2009).

    Article  CAS  Google Scholar 

  11. Goldman-Rakic, P. S. Cellular basis of working memory. Neuron 14, 477–485 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Lisman, J. E., Fellous, J. M. & Wang, X. J. A role for NMDA-receptor channels in working memory. Nature Neurosci. 1, 273–275 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Milad, M. R. et al. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol. Psychiatry 62, 446–454 (2007).

    Article  PubMed  Google Scholar 

  14. Milad, M. R. & Quirk, G. J. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420, 70–74 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Goto, Y., Yang, C. R. & Otani, S. Functional and dysfunctional synaptic plasticity in prefrontal cortex: roles in psychiatric disorders. Biol. Psychiatry 67, 199–207 (2010).

    Article  PubMed  Google Scholar 

  16. Hains, A. B. & Arnsten, A. F. Molecular mechanisms of stress-induced prefrontal cortical impairment: implications for mental illness. Learn. Mem. 15, 551–564 (2008).

    Article  PubMed  Google Scholar 

  17. Moghaddam, B. Bringing order to the glutamate chaos in schizophrenia. Neuron 40, 881–884 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Joels, M. & Baram, T. Z. The neuro-symphony of stress. Nature Rev. Neurosci. 10, 459–466 (2009).

    Article  CAS  Google Scholar 

  19. Roozendaal, B., McEwen, B. S. & Chattarji, S. Stress, memory and the amygdala. Nature Rev. Neurosci. 10, 423–433 (2009).

    Article  CAS  Google Scholar 

  20. Joiner, M. L. et al. Assembly of a β2-adrenergic receptor-GluR1 signalling complex for localized cAMP signalling. EMBO J. 29, 482–495 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Erecinska, M. & Silver, I. A. Metabolism and role of glutamate in mammalian brain. Prog. Neurobiol. 35, 245–296 (1990).

    Article  CAS  PubMed  Google Scholar 

  22. Lang, T. & Jahn, R. Core proteins of the secretory machinery. Handb. Exp. Pharmacol. 184, 107–127 (2008).

    Article  CAS  Google Scholar 

  23. Rizo, J. & Rosenmund, C. Synaptic vesicle fusion. Nature Struct. Mol. Biol. 15, 665–674 (2008).

    Article  CAS  Google Scholar 

  24. Sudhof, T. C. & Rothman, J. E. Membrane fusion: grappling with SNARE and SM proteins. Science 323, 474–477 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Roche, K. W. et al. Molecular determinants of NMDA receptor internalization. Nature Neurosci. 4, 794–802 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Hayashi, Y. et al. Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 287, 2262–2267 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Elias, G. M. et al. Synapse-specific and developmentally regulated targeting of AMPA receptors by a family of MAGUK scaffolding proteins. Neuron 52, 307–320 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Lee, S. H., Liu, L., Wang, Y. T. & Sheng, M. Clathrin adaptor AP2 and NSF interact with overlapping sites of GluR2 and play distinct roles in AMPA receptor trafficking and hippocampal LTD. Neuron 36, 661–674 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Prybylowski, K. et al. The synaptic localization of NR2B-containing NMDA receptors is controlled by interactions with PDZ proteins and AP-2. Neuron 47, 845–857 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bhattacharyya, S., Biou, V., Xu, W., Schluter, O. & Malenka, R. C. A critical role for PSD-95/AKAP interactions in endocytosis of synaptic AMPA receptors. Nature Neurosci. 12, 172–181 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Setou, M., Nakagawa, T., Seog, D. H. & Hirokawa, N. Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport. Science 288, 1796–1802 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Setou, M. et al. Glutamate-receptor-interacting protein GRIP1 directly steers kinesin to dendrites. Nature 417, 83–87 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Wang, Z. et al. Myosin Vb mobilizes recycling endosomes and AMPA receptors for postsynaptic plasticity. Cell 135, 535–548 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pfeffer, S. & Aivazian, D. Targeting Rab GTPases to distinct membrane compartments. Nature Rev. Mol. Cell Biol. 5, 886–896 (2004).

    Article  CAS  Google Scholar 

  35. Brown, T. C., Tran, I. C., Backos, D. S. & Esteban, J. A. NMDA receptor-dependent activation of the small GTPase Rab5 drives the removal of synaptic AMPA receptors during hippocampal LTD. Neuron 45, 81–94 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Park, M., Penick, E. C., Edwards, J. G., Kauer, J. A. & Ehlers, M. D. Recycling endosomes supply AMPA receptors for LTP. Science 305, 1972–1975 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Liu, Y. et al. A single fear-inducing stimulus induces a transcription-dependent switch in synaptic AMPAR phenotype. Nature Neurosci. 13, 223–231 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Hawasli, A. H. et al. Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. Nature Neurosci. 10, 880–886 (2007).

    CAS  PubMed  Google Scholar 

  39. O'Shea, R. D. Roles and regulation of glutamate transporters in the central nervous system. Clin. Exp. Pharmacol. Physiol. 29, 1018–1023 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Lowy, M. T., Gault, L. & Yamamoto, B. K. Adrenalectomy attenuates stress-induced elevations in extracellular glutamate concentrations in the hippocampus. J. Neurochem. 61, 1957–1960 (1993).

    Article  CAS  PubMed  Google Scholar 

  41. Lowy, M. T., Wittenberg, L. & Yamamoto, B. K. Effect of acute stress on hippocampal glutamate levels and spectrin proteolysis in young and aged rats. J. Neurochem. 65, 268–274 (1995).

    Article  CAS  PubMed  Google Scholar 

  42. Venero, C. & Borrell, J. Rapid glucocorticoid effects on excitatory amino acid levels in the hippocampus: a microdialysis study in freely moving rats. Eur. J. Neurosci. 11, 2465–2473 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Reznikov, L. R. et al. Acute stress-mediated increases in extracellular glutamate levels in the rat amygdala: differential effects of antidepressant treatment. Eur. J. Neurosci. 25, 3109–3114 (2007).

    Article  PubMed  Google Scholar 

  44. Bagley, J. & Moghaddam, B. Temporal dynamics of glutamate efflux in the prefrontal cortex and in the hippocampus following repeated stress: effects of pretreatment with saline or diazepam. Neuroscience 77, 65–73 (1997).

    Article  CAS  PubMed  Google Scholar 

  45. Moghaddam, B. Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia. J. Neurochem. 60, 1650–1657 (1993).

    Article  CAS  PubMed  Google Scholar 

  46. Westerink, B. H. Brain microdialysis and its application for the study of animal behaviour. Behav. Brain Res. 70, 103–124 (1995).

    Article  CAS  PubMed  Google Scholar 

  47. Timmerman, W. & Westerink, B. H. Brain microdialysis of GABA and glutamate: what does it signify? Synapse 27, 242–261 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. Hascup, E. R. et al. Rapid microelectrode measurements and the origin and regulation of extracellular glutamate in rat prefrontal cortex. J. Neurochem. 115, 1608–1620 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Karst, H. et al. Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. Proc. Natl Acad. Sci. USA 102, 19204–19207 (2005). This study used patch-clamp recordings to show that applying corticosterone onto hippocampal slices rapidly and reversibly enhances glutamate release and transmission through a non-genomic pathway involving membrane-located mineralocorticoid receptors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. de Kloet, E. R., Karst, H. & Joels, M. Corticosteroid hormones in the central stress response: quick-and-slow. Front. Neuroendocrinol. 29, 268–272 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Mallei, A. et al. Synaptoproteomics of learned helpless rats involve energy metabolism and cellular remodeling pathways in depressive-like behavior and antidepressant response. Neuropharmacology 60, 1243–1253 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Musazzi, L. et al. Acute stress increases depolarization-evoked glutamate release in the rat prefrontal/frontal cortex: the dampening action of antidepressants. PLoS ONE 5, e8566 (2010). This study used purified synaptosomes in superfusion and patch-clamp recordings to show that acute stress, through increased corticosterone levels, glucocorticoid receptor activation and accumulation of presynaptic SNARE complexes in synaptic membranes, rapidly enhances depolarization-evoked release of glutamate in the PFC and frontal cortex. The enhancement of glutamate release was prevented by previous treatments with antidepressant agents.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang, C. C. & Wang, S. J. Modulation of presynaptic glucocorticoid receptors on glutamate release from rat hippocampal nerve terminals. Synapse 63, 745–751 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Hill, M. N. et al. Recruitment of prefrontal cortical endocannabinoid signaling by glucocorticoids contributes to termination of the stress response. J. Neurosci. 31, 10506–10515 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rizzoli, S. O. & Betz, W. J. Synaptic vesicle pools. Nature Rev. Neurosci. 6, 57–69 (2005).

    Article  CAS  Google Scholar 

  56. Sorensen, J. B. Formation, stabilisation and fusion of the readily releasable pool of secretory vesicles. Pflugers Arch. 448, 347–362 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Matz, J., Gilyan, A., Kolar, A., McCarvill, T. & Krueger, S. R. Rapid structural alterations of the active zone lead to sustained changes in neurotransmitter release. Proc. Natl Acad. Sci. USA 107, 8836–8841 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lonart, G. & Sudhof, T. C. Assembly of SNARE core complexes prior to neurotransmitter release sets the readily releasable pool of synaptic vesicles. J. Biol. Chem. 275, 27703–27707 (2000).

    CAS  PubMed  Google Scholar 

  59. Popoli, M. et al. Acute behavioural stress affects the readily releasable pool of vesicles in prefrontal/frontal cortex. Soc. Neurosci. Abstr. 667.7 (San Diego, California, 13–17 Nov 2010).

  60. Martens, S., Kozlov, M. M. & McMahon, H. T. How synaptotagmin promotes membrane fusion. Science 316, 1205–1208 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Chicka, M. C., Hui, E., Liu, H. & Chapman, E. R. Synaptotagmin arrests the SNARE complex before triggering fast, efficient membrane fusion in response to Ca2+. Nature Struct. Mol. Biol. 15, 827–835 (2008).

    Article  CAS  Google Scholar 

  62. Xue, M. et al. Complexins facilitate neurotransmitter release at excitatory and inhibitory synapses in mammalian central nervous system. Proc. Natl Acad. Sci. USA 105, 7875–7880 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Giraudo, C. G. et al. Alternative zippering as an on-off switch for SNARE-mediated fusion. Science 323, 512–516 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sanacora, G., Treccani, G. & Popoli, M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 62, 63–77 (2012). This review summarizes the compelling evidence for a primary involvement of the glutamate system in the pathophysiology of mood and anxiety disorders and in psychotropic drug action. The article proposes a paradigm shift from the traditional monoaminergic hypothesis to a neuroplasticity hypothesis focussed on glutamate, which may represent a substantial advancement for research on new drugs and therapies.

    Article  CAS  PubMed  Google Scholar 

  65. Moghaddam, B. Stress activation of glutamate neurotransmission in the prefrontal cortex: implications for dopamine-associated psychiatric disorders. Biol. Psychiatry 51, 775–787 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Yamamoto, B. K. & Reagan, L. P. The glutamatergic system in neuronal plasticity and vulnerability in mood disorders. Neuropsychiatr. Dis. Treat. 2, 7–14 (2006).

    Google Scholar 

  67. Yuen, E. Y. et al. Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory. Proc. Natl Acad. Sci. USA 106, 14075–14079 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Yuen, E. Y. et al. Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory. Mol. Psychiatry 16, 156–170 (2011). This paper, together with reference 67, shows that acute stress increases glutamatergic synaptic transmission and membrane trafficking of NMDARs and AMPARs in PFC neurons via glucocorticoid receptor–SGK–RAB4 signalling, thus facilitating cognitive processes mediated by the PFC.

    Article  CAS  PubMed  Google Scholar 

  69. Liu, W., Yuen, E. Y. & Yan, Z. The stress hormone corticosterone increases synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors via serum- and glucocorticoid-inducible kinase (SGK) regulation of the GDI–Rab4 complex. J. Biol. Chem. 285, 6101–6108 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Olijslagers, J. E. et al. Rapid changes in hippocampal CA1 pyramidal cell function via pre- as well as postsynaptic membrane mineralocorticoid receptors. Eur. J. Neurosci. 27, 2542–2550 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. de Kloet, E. R., Joels, M. & Holsboer, F. Stress and the brain: from adaptation to disease. Nature Rev. Neurosci. 6, 463–475 (2005).

    Article  CAS  Google Scholar 

  72. Karst, H. & Joels, M. Corticosterone slowly enhances miniature excitatory postsynaptic current amplitude in mice CA1 hippocampal cells. J. Neurophysiol. 94, 3479–3486 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Saal, D., Dong, Y., Bonci, A. & Malenka, R. C. Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37, 577–582 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Campioni, M. R., Xu, M. & McGehee, D. S. Stress-induced changes in nucleus accumbens glutamate synaptic plasticity. J. Neurophysiol. 101, 3192–3198 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yuen, E. Y., Wei, J. & Yan, Z. Repeated stress suppresses glutamate receptor expression and function in prefrontal cortex and impairs object recognition memory. Soc. Neurosci. Abstr. 389.21 (San Diego, California, 13–17 Nov 2010).

  76. Karst, H. & Joels, M. Effect of chronic stress on synaptic currents in rat hippocampal dentate gyrus neurons. J. Neurophysiol. 89, 625–633 (2003).

    Article  PubMed  Google Scholar 

  77. Maroun, M. & Richter-Levin, G. Exposure to acute stress blocks the induction of long-term potentiation of the amygdala-prefrontal cortex pathway in vivo. J. Neurosci. 23, 4406–4409 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Rocher, C., Spedding, M., Munoz, C. & Jay, T. M. Acute stress-induced changes in hippocampal/prefrontal circuits in rats: effects of antidepressants. Cereb. Cortex 14, 224–229 (2004).

    Article  PubMed  Google Scholar 

  79. Mailliet, F. et al. Protection of stress-induced impairment of hippocampal/prefrontal LTP through blockade of glucocorticoid receptors: implication of MEK signaling. Exp. Neurol. 211, 593–596 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Richter-Levin, G. & Maroun, M. Stress and amygdala suppression of metaplasticity in the medial prefrontal cortex. Cereb. Cortex 20, 2433–2441 (2010).

    Article  PubMed  Google Scholar 

  81. Hirata, R. et al. Possible relationship between the stress-induced synaptic response and metaplasticity in the hippocampal CA1 field of freely moving rats. Synapse 63, 549–556 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Chaouloff, F., Hemar, A. & Manzoni, O. Acute stress facilitates hippocampal CA1 metabotropic glutamate receptor-dependent long-term depression. J. Neurosci. 27, 7130–7135 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 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. 586, 4465–4479 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Quan, M. et al. Impairments of behavior, information flow between thalamus and cortex, and prefrontal cortical synaptic plasticity in an animal model of depression. Brain Res. Bull. 85, 109–116 (2011).

    Article  PubMed  Google Scholar 

  85. Cerqueira, J. J., Mailliet, F., Almeida, O. F., Jay, T. M. & Sousa, N. The prefrontal cortex as a key target of the maladaptive response to stress. J. Neurosci. 27, 2781–2787 (2007). This paper shows that chronic stress impairs synaptic plasticity in the hippocampal–PFC connection, induces selective atrophy in the PFC and disrupts working memory and behavioural flexibility, thus establishing a fundamental role of the PFC in maladaptive responses to chronic stress.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Goldwater, D. S. et al. Structural and functional alterations to rat medial prefrontal cortex following chronic restraint stress and recovery. Neuroscience 164, 798–808 (2009).

    Article  CAS  PubMed  Google Scholar 

  87. Judo, C. et al. Early stress exposure impairs synaptic potentiation in the rat medial prefrontal cortex underlying contextual fear extinction. Neuroscience 169, 1705–1714 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Malinow, R. & Malenka, R. C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Wenthold, R. J., Prybylowski, K., Standley, S., Sans, N. & Petralia, R. S. Trafficking of NMDA receptors. Annu. Rev. Pharmacol. Toxicol. 43, 335–358 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Groc, L., Choquet, D. & Chaouloff, F. The stress hormone corticosterone conditions AMPAR surface trafficking and synaptic potentiation. Nature Neurosci. 11, 868–870 (2008). This paper used single quantum-dot imaging to show that corticosterone triggers time-dependent increases in GluR2 surface mobility and synaptic content via distinct corticosteroid receptors, thus revealing the influence of corticosterone on AMPAR trafficking in hippocampal cultures.

    Article  CAS  PubMed  Google Scholar 

  91. Martin, S. et al. Corticosterone alters AMPAR mobility and facilitates bidirectional synaptic plasticity. PLoS ONE 4, e4714 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Conboy, L. & Sandi, C. Stress at learning facilitates memory formation by regulating AMPA receptor trafficking through a glucocorticoid action. Neuropsychopharmacology 35, 674–685 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Gourley, S. L., Kedves, A. T., Olausson, P. & Taylor, J. R. A history of corticosterone exposure regulates fear extinction and cortical NR2B, GluR2/3, and BDNF. Neuropsychopharmacology 34, 707–716 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Funder, J. W. Glucocorticoid and mineralocorticoid receptors: biology and clinical relevance. Annu. Rev. Med. 48, 231–240 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Firestone, G. L., Giampaolo, J. R. & O'Keeffe, B. A. Stimulus-dependent regulation of serum and glucocorticoid inducible protein kinase (SGK) transcription, subcellular localization and enzymatic activity. Cell. Physiol. Biochem. 13, 1–12 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Lang, F. et al. (Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms. Physiol. Rev. 86, 1151–1178 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Tsai, K. J., Chen, S. K., Ma, Y. L., Hsu, W. L. & Lee, E. H. sgk, a primary glucocorticoid-induced gene, facilitates memory consolidation of spatial learning in rats. Proc. Natl Acad. Sci. USA 99, 3990–3995 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. van der Sluijs, P. et al. The small GTP-binding protein rab4 controls an early sorting event on the endocytic pathway. Cell 70, 729–740 (1992).

    Article  CAS  PubMed  Google Scholar 

  99. Zerial, M. & McBride, H. Rab proteins as membrane organizers. Nature Rev. Mol. Cell Biol. 2, 107–117 (2001).

    Article  CAS  Google Scholar 

  100. Sasaki, T. et al. Purification and characterization from bovine brain cytosol of a protein that inhibits the dissociation of GDP from and the subsequent binding of GTP to smg p25A, a ras p21-like GTP-binding protein. J. Biol. Chem. 265, 2333–2337 (1990).

    CAS  PubMed  Google Scholar 

  101. Wu, Y. W. et al. Membrane targeting mechanism of Rab GTPases elucidated by semisynthetic protein probes. Nature Chem. Biol. 6, 534–540 (2010).

    Article  CAS  Google Scholar 

  102. van Gemert, N. G., Meijer, O. C., Morsink, M. C. & Joels, M. Effect of brief corticosterone administration on SGK1 and RGS4 mRNA expression in rat hippocampus. Stress 9, 165–170 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Revest, J. M. et al. The MAPK pathway and Egr-1 mediate stress-related behavioral effects of glucocorticoids. Nature Neurosci. 8, 664–672 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Fumagalli, F. et al. AMPA GluR-A receptor subunit mediates hippocampal responsiveness in mice exposed to stress. Hippocampus 21, 1028–1035 (2011).

    CAS  PubMed  Google Scholar 

  105. Chowdhury, S. et al. Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron 52, 445–459 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Messaoudi, E. et al. Sustained Arc/Arg3.1 synthesis controls long-term potentiation consolidation through regulation of local actin polymerization in the dentate gyrus in vivo. J. Neurosci. 27, 10445–10455 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Mabb, A. M. & Ehlers, M. D. Ubiquitination in postsynaptic function and plasticity. Annu. Rev. Cell Dev. Biol. 26, 179–210 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Krugers, H. J., Hoogenraad, C. C. & Groc, L. Stress hormones and AMPA receptor trafficking in synaptic plasticity and memory. Nature Rev. Neurosci. 11, 675–681 (2010).

    Article  CAS  Google Scholar 

  109. Van den Oever, M. C. et al. Prefrontal cortex AMPA receptor plasticity is crucial for cue-induced relapse to heroin-seeking. Nature Neurosci. 11, 1053–1058 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Lupien, S. J. et al. The modulatory effects of corticosteroids on cognition: studies in young human populations. Psychoneuroendocrinology 27, 401–416 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Henckens, M. J., van Wingen, G. A., Joels, M. & Fernandez, G. Time-dependent corticosteroid modulation of prefrontal working memory processing. Proc. Natl Acad. Sci. USA 108, 5801–5806 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Smeets, T., Giesbrecht, T., Jelicic, M. & Merckelbach, H. Context-dependent enhancement of declarative memory performance following acute psychosocial stress. Biol. Psychol. 76, 116–123 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Cerqueira, J. J. et al. Morphological correlates of corticosteroid-induced changes in prefrontal cortex-dependent behaviors. J. Neurosci. 25, 7792–7800 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Young, A. H., Sahakian, B. J., Robbins, T. W. & Cowen, P. J. The effects of chronic administration of hydrocortisone on cognitive function in normal male volunteers. Psychopharmacology 145, 260–266 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. Liston, C., McEwen, B. S. & Casey, B. J. Psychosocial stress reversibly disrupts prefrontal processing and attentional control. Proc. Natl Acad. Sci. USA 106, 912–917 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. McEwen, B. S. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol. Rev. 87, 873–904 (2007).

    Article  PubMed  Google Scholar 

  117. Tzingounis, A. V. & Wadiche, J. I. Glutamate transporters: confining runaway excitation by shaping synaptic transmission. Nature Rev. Neurosci. 8, 935–947 (2007).

    Article  CAS  Google Scholar 

  118. Zheng, K., Scimemi, A. & Rusakov, D. A. Receptor actions of synaptically released glutamate: the role of transporters on the scale from nanometers to microns. Biophys. J. 95, 4584–4596 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Piet, R., Vargova, L., Sykova, E., Poulain, D. A. & Oliet, S. H. Physiological contribution of the astrocytic environment of neurons to intersynaptic crosstalk. Proc. Natl Acad. Sci. USA 101, 2151–2155 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hardingham, G. E. & Bading, H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nature Rev. Neurosci. 11, 682–696 (2010). The Review provides a comprehensive overview of the converging evidence supporting the unique and sometimes opposing roles of synaptic and extrasynaptic NMDARs in mediating effects on neuronal plasticity and resiliency.

    Article  CAS  Google Scholar 

  121. Hardingham, G. E., Fukunaga, Y. & Bading, H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nature Neurosci. 5, 405–414 (2002).

    Article  CAS  PubMed  Google Scholar 

  122. Vanhoutte, P. & Bading, H. Opposing roles of synaptic and extrasynaptic NMDA receptors in neuronal calcium signalling and BDNF gene regulation. Curr. Opin. Neurobiol. 13, 366–371 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Ivanov, A. et al. Opposing role of synaptic and extrasynaptic NMDA receptors in regulation of the extracellular signal-regulated kinases (ERK) activity in cultured rat hippocampal neurons. J. Physiol. 572, 789–798 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Leveille, F. et al. Neuronal viability is controlled by a functional relation between synaptic and extrasynaptic NMDA receptors. FASEB J. 22, 4258–4271 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Xu, J. et al. Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP. J. Neurosci. 29, 9330–9343 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Omrani, A. et al. Up-regulation of GLT-1 severely impairs LTD at mossy fibre-CA3 synapses. J. Physiol. 587, 4575–4588 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Beart, P. M. & O'Shea, R. D. Transporters for L-glutamate: an update on their molecular pharmacology and pathological involvement. Br. J. Pharmacol. 150, 5–17 (2007).

    Article  CAS  PubMed  Google Scholar 

  128. Bushong, E. A., Martone, M. E., Jones, Y. Z. & Ellisman, M. H. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J. Neurosci. 22, 183–192 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Ogata, K. & Kosaka, T. Structural and quantitative analysis of astrocytes in the mouse hippocampus. Neuroscience 113, 221–233 (2002).

    Article  CAS  PubMed  Google Scholar 

  130. Ongur, D., Drevets, W. C. & Price, J. L. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc. Natl Acad. Sci. USA 95, 13290–13295 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Cotter, D. et al. Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb. Cortex 12, 386–394 (2002).

    Article  PubMed  Google Scholar 

  132. Rajkowska, G. & Miguel-Hidalgo, J. J. Gliogenesis and glial pathology in depression. CNS Neurol. Disord. Drug Targets 6, 219–233 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Miguel-Hidalgo, J. J. et al. Glial fibrillary acidic protein immunoreactivity in the prefrontal cortex distinguishes younger from older adults in major depressive disorder. Biol. Psychiatry 48, 861–873 (2000).

    Article  CAS  PubMed  Google Scholar 

  134. Webster, M. J. et al. Immunohistochemical localization of phosphorylated glial fibrillary acidic protein in the prefrontal cortex and hippocampus from patients with schizophrenia, bipolar disorder, and depression. Brain Behav. Immun. 15, 388–400 (2001).

    Article  CAS  PubMed  Google Scholar 

  135. Fatemi, S. H. et al. Glial fibrillary acidic protein is reduced in cerebellum of subjects with major depression, but not schizophrenia. Schizophr. Res. 69, 317–323 (2004).

    Article  PubMed  Google Scholar 

  136. Miguel-Hidalgo, J. J. et al. Glial and glutamatergic markers in depression, alcoholism, and their comorbidity. J. Affect. Disord. 127, 230–240 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Altshuler, L. L. et al. Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorder. Bipolar Disord. 12, 541–549 (2010).

    Article  PubMed  Google Scholar 

  138. Middeldorp, J. & Hol, E. M. GFAP in health and disease. Prog. Neurobiol. 93, 421–443 (2011).

    Article  CAS  PubMed  Google Scholar 

  139. Sanacora, G. et al. Reduced cortical γ-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch. Gen. Psychiatry 56, 1043–1047 (1999).

    Article  CAS  PubMed  Google Scholar 

  140. Sanacora, G. et al. Subtype-specific alterations of GABA and glutamate in major depression. Arch. Gen. Psychiatry 61, 705–713 (2004).

    Article  CAS  PubMed  Google Scholar 

  141. Banasr, M. et al. Chronic unpredictable stress decreases cell proliferation in the cerebral cortex of the adult rat. Biol. Psychiatry 62, 496–504 (2007).

    Article  CAS  PubMed  Google Scholar 

  142. Banasr, M. & Duman, R. S. glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol. Psychiatry 64, 863–870 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Leventopoulos, M. et al. Long-term effects of early life deprivation on brain glia in Fischer rats. Brain Res. 1142, 119–126 (2007).

    Article  CAS  PubMed  Google Scholar 

  144. Fuchs, E. Social stress in tree shrews as an animal model of depression: an example of a behavioral model of a CNS disorder. CNS Spectr. 10, 182–190 (2005).

    Article  PubMed  Google Scholar 

  145. Liu, Q. et al. Glia atrophy in the hippocampus of chronic unpredictable stress-induced depression model rats is reversed by electroacupuncture treatment. J. Affect. Disord. 128, 309–313 (2011).

    Article  CAS  PubMed  Google Scholar 

  146. Kwon, S. K. et al. Stress and traumatic brain injury: a behavioral, proteomics, and histological study. Front. Neurol. 2, 12 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Jang, S., Suh, S. H., Yoo, H. S., Lee, Y. M. & Oh, S. Changes in iNOS, GFAP and NR1 expression in various brain regions and elevation of sphingosine-1-phosphate in serum after immobilized stress. Neurochem. Res. 33, 842–851 (2008).

    Article  CAS  PubMed  Google Scholar 

  148. O'Callaghan, J. P., Brinton, R. E. & McEwen, B. S. Glucocorticoids regulate the synthesis of glial fibrillary acidic protein in intact and adrenalectomized rats but do not affect its expression following brain injury. J. Neurochem. 57, 860–869 (1991).

    Article  CAS  PubMed  Google Scholar 

  149. Nichols, N. R., Osterburg, H. H., Masters, J. N., Millar, S. L. & Finch, C. E. Messenger RNA for glial fibrillary acidic protein is decreased in rat brain following acute and chronic corticosterone treatment. Brain Res. Mol. Brain Res. 7, 1–7 (1990).

    Article  CAS  PubMed  Google Scholar 

  150. Ramos-Remus, C., Gonzalez-Castaneda, R. E., Gonzalez-Perez, O., Luquin, S. & Garcia-Estrada, J. Prednisone induces cognitive dysfunction, neuronal degeneration, and reactive gliosis in rats. J. Investig. Med. 50, 458–464 (2002).

    Article  CAS  PubMed  Google Scholar 

  151. Bridges, N., Slais, K. & Sykova, E. The effects of chronic corticosterone on hippocampal astrocyte numbers: a comparison of male and female Wistar rats. Acta Neurobiol. Exp. 68, 131–138 (2008).

    Google Scholar 

  152. Hughes, E. G., Maguire, J. L., McMinn, M. T., Scholz, R. E. & Sutherland, M. L. Loss of glial fibrillary acidic protein results in decreased glutamate transport and inhibition of PKA-induced EAAT2 cell surface trafficking. Brain Res. Mol. Brain Res. 124, 114–123 (2004).

    Article  CAS  PubMed  Google Scholar 

  153. Gilad, G. M., Gilad, V. H., Wyatt, R. J. & Tizabi, Y. Region-selective stress-induced increase of glutamate uptake and release in rat forebrain. Brain Res. 525, 335–338 (1990).

    Article  CAS  PubMed  Google Scholar 

  154. Yang, C. H., Huang, C. C. & Hsu, K. S. Behavioral stress enhances hippocampal CA1 long-term depression through the blockade of the glutamate uptake. J. Neurosci. 25, 4288–4293 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Fontella, F. U. et al. Repeated restraint stress alters hippocampal glutamate uptake and release in the rat. Neurochem. Res. 29, 1703–1709 (2004).

    Article  CAS  PubMed  Google Scholar 

  156. Olivenza, R. et al. Chronic stress induces the expression of inducible nitric oxide synthase in rat brain cortex. J. Neurochem. 74, 785–791 (2000).

    Article  CAS  PubMed  Google Scholar 

  157. de Vasconcellos-Bittencourt, A. P. et al. Chronic stress and lithium treatments alter hippocampal glutamate uptake and release in the rat and potentiate necrotic cellular death after oxygen and glucose deprivation. Neurochem. Res. 36, 793–800 (2011).

    Article  CAS  PubMed  Google Scholar 

  158. Almeida, R. F. et al. Effects of depressive-like behavior of rats on brain glutamate uptake. Neurochem. Res. 35, 1164–1171 (2010).

    Article  CAS  PubMed  Google Scholar 

  159. Zink, M., Vollmayr, B., Gebicke-Haerter, P. J. & Henn, F. A. Reduced expression of glutamate transporters vGluT1, EAAT2 and EAAT4 in learned helpless rats, an animal model of depression. Neuropharmacology 58, 465–473 (2010).

    Article  CAS  PubMed  Google Scholar 

  160. Autry, A. E. et al. Glucocorticoid regulation of GLT-1 glutamate transporter isoform expression in the rat hippocampus. Neuroendocrinology 83, 371–379 (2006).

    Article  CAS  PubMed  Google Scholar 

  161. Zschocke, J. et al. Differential promotion of glutamate transporter expression and function by glucocorticoids in astrocytes from various brain regions. J. Biol. Chem. 280, 34924–34932 (2005).

    Article  CAS  PubMed  Google Scholar 

  162. Allritz, C., Bette, S., Figiel, M. & Engele, J. Comparative structural and functional analysis of the GLT-1/EAAT-2 promoter from man and rat. J. Neurosci. Res. 88, 1234–1241 (2010).

    CAS  PubMed  Google Scholar 

  163. Grippo, A. J., Francis, J., Beltz, T. G., Felder, R. B. & Johnson, A. K. Neuroendocrine and cytokine profile of chronic mild stress-induced anhedonia. Physiol. Behav. 84, 697–706 (2005).

    Article  CAS  PubMed  Google Scholar 

  164. Carmen, J., Rothstein, J. D. & Kerr, D. A. Tumor necrosis factor-α modulates glutamate transport in the CNS and is a critical determinant of outcome from viral encephalomyelitis. Brain Res. 1263, 143–154 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Tolosa, L., Caraballo-Miralles, V., Olmos, G. & Llado, J. TNF-α potentiates glutamate-induced spinal cord motoneuron death via NF-κB. Mol. Cell. Neurosci. 46, 176–186 (2011).

    Article  CAS  PubMed  Google Scholar 

  166. Nakagawa, T., Otsubo, Y., Yatani, Y., Shirakawa, H. & Kaneko, S. Mechanisms of substrate transport-induced clustering of a glial glutamate transporter GLT-1 in astroglial-neuronal cultures. Eur. J. Neurosci. 28, 1719–1730 (2008).

    Article  PubMed  Google Scholar 

  167. Zhou, J. & Sutherland, M. L. Glutamate transporter cluster formation in astrocytic processes regulates glutamate uptake activity. J. Neurosci. 24, 6301–6306 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Choudary, P. V. et al. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc. Natl Acad. Sci. USA 102, 15653–15658 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Bernard, R. et al. Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression. Mol. Psychiatry 16, 634–646 (2011).

    Article  CAS  PubMed  Google Scholar 

  170. Sequeira, A. et al. Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS ONE 4, e6585 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Banasr, M. et al. Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. Mol. Psychiatry 15, 501–511 (2010). This study shows that chronic unpredictable stress influences glial cell metabolism and amino acid neurotransmitter cycling, and that riluzole — a drug that modulates glutamate release and uptake — can reverse the effects of stress on glial cell metabolism, glutamate–glutamine cycling and behaviour.

    Article  CAS  PubMed  Google Scholar 

  172. Rajkowska, G. Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol. Psychiatry 48, 766–777 (2000).

    Article  CAS  PubMed  Google Scholar 

  173. Rajkowska, G. Cell pathology in mood disorders. Semin. Clin. Neuropsychiatry 7, 281–292 (2002).

    Article  PubMed  Google Scholar 

  174. Musazzi, L., Racagni, G. & Popoli, M. Stress, glucocorticoids and glutamate release: effects of antidepressant drugs. Neurochem. Int. 59, 138–149 (2011).

    Article  CAS  PubMed  Google Scholar 

  175. van Tol, M. J. et al. Regional brain volume in depression and anxiety disorders. Arch. Gen. Psychiatry 67, 1002–1011 (2010).

    Article  PubMed  Google Scholar 

  176. Cavus, I. et al. Decreased hippocampal volume on MRI is associated with increased extracellular glutamate in epilepsy patients. Epilepsia 49, 1358–1366 (2008).

    Article  PubMed  Google Scholar 

  177. Shors, T. J., Weiss, C. & Thompson, R. F. Stress-induced facilitation of classical conditioning. Science 257, 537–539 (1992).

    Article  CAS  PubMed  Google Scholar 

  178. Beylin, A. V. & Shors, T. J. Glucocorticoids are necessary for enhancing the acquisition of associative memories after acute stressful experience. Horm. Behav. 43, 124–131 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Sanacora, G., Zarate, C. A., Krystal, J. H. & Manji, H. K. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nature Rev. Drug Discov. 7, 426–437 (2008).

    Article  CAS  Google Scholar 

  180. Fumagalli, E., Funicello, M., Rauen, T., Gobbi, M. & Mennini, T. Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. Eur. J. Pharmacol. 578, 171–176 (2008).

    Article  CAS  PubMed  Google Scholar 

  181. Sung, B., Lim, G. & Mao, J. Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J. Neurosci. 23, 2899–2910 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Frizzo, M. E., Dall'Onder, L. P., Dalcin, K. B. & Souza, D. O. Riluzole enhances glutamate uptake in rat astrocyte cultures. Cell. Mol. Neurobiol. 24, 123–128 (2004).

    Article  CAS  PubMed  Google Scholar 

  183. Rothstein, J. D. et al. β-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433, 73–77 (2005).

    Article  CAS  PubMed  Google Scholar 

  184. Mineur, Y. S., Picciotto, M. R. & Sanacora, G. Antidepressant-like effects of ceftriaxone in male C57BL/56J mice. Biol. Psychiatry 61, 250–252 (2007).

    Article  CAS  PubMed  Google Scholar 

  185. Gourley, S. L., Espitia, J. W., Sanacora, G. & Taylor, J. R. Utility and antidepressant-like properties of oral riluzole in mice. Psychopharmacology 21 Jul 2011 (doi:10.1007/s00213-011-2403–2404).

  186. Krystal, J. H. et al. Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. CNS Drugs 24, 669–693 (2010).

    Article  CAS  PubMed  Google Scholar 

  187. Machado-Vieira, R., Salvadore, G., Ibrahim, L. A., Diaz-Granados, N. & Zarate, C. A. Jr. Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders. Curr. Pharm. Des. 15, 1595–1611 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Li, N. et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329, 959–964 (2010). This study demonstrates AMPAR-mediated effects of NMDAR antagonists on synaptic plasticity and behaviour. The paper provides strong evidence to suggest that the antidepressant and anti-stress effects of NMDAR antagonists such as ketamine are, at least in part, mediated by increased excitation of postsynaptic AMPARs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Autry, A. E. et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475, 91–95 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Koike, H., Iijima, M. & Chaki, S. Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav. Brain Res. 224, 107–111 (2011).

    Article  CAS  PubMed  Google Scholar 

  191. Li, N. et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol. Psychiatry 69, 754–761 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Farley, S., Apazoglou, K., Witkin, J. M., Giros, B. & Tzavara, E. T. Antidepressant-like effects of an AMPA receptor potentiator under a chronic mild stress paradigm. Int. J. Neuropsychopharmacol. 13, 1207–1218 (2010).

    Article  CAS  PubMed  Google Scholar 

  193. Haller, J., Mikics, E. & Makara, G. B. The effects of non-genomic glucocorticoid mechanisms on bodily functions and the central neural system. A critical evaluation of findings. Front. Neuroendocrinol. 29, 273–291 (2008).

    Article  CAS  PubMed  Google Scholar 

  194. Yamamoto, K. R. Steroid receptor regulated transcription of specific genes and gene networks. Annu. Rev. Genet. 19, 209–252 (1985).

    Article  CAS  PubMed  Google Scholar 

  195. Levin, E. R. Membrane oestrogen receptor α signalling to cell functions. J. Physiol. 587, 5019–5023 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Pietras, R. J., Nemere, I. & Szego, C. M. Steroid hormone receptors in target cell membranes. Endocrine 14, 417–427 (2001).

    Article  CAS  PubMed  Google Scholar 

  197. Ahima, R., Krozowski, Z. & Harlan, R. Type I corticosteroid receptor-like immunoreactivity in the rat CNS: distribution and regulation by corticosteroids. J. Comp. Neurol. 313, 522–538 (1991).

    Article  CAS  PubMed  Google Scholar 

  198. Ahima, R. S. & Harlan, R. E. Charting of type II glucocorticoid receptor-like immunoreactivity in the rat central nervous system. Neuroscience 39, 579–604 (1990).

    Article  CAS  PubMed  Google Scholar 

  199. Johnson, L. R., Farb, C., Morrison, J. H., McEwen, B. S. & LeDoux, J. E. Localization of glucocorticoid receptors at postsynaptic membranes in the lateral amygdala. Neuroscience 136, 289–299 (2005).

    Article  CAS  PubMed  Google Scholar 

  200. Orchinik, M., Murray, T. F., Franklin, P. H. & Moore, F. L. Guanyl nucleotides modulate binding to steroid receptors in neuronal membranes. Proc. Natl Acad. Sci. USA 89, 3830–3834 (1992). A key paper showing G-protein-like glucocorticoid receptors in the brain of a newt, Taricha granulosa , which led to the finding of rapid glucocorticoid signalling for the endocannabinoid systems summarized in reference 201. However, recent work (reference 209) showing Ru486 antagonism in the glucocorticoid regulation of endocannabinoids raises questions about the involvement of classical glucocorticoid receptors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Tasker, J. G., Di, S. & Malcher-Lopes, R. Minireview: rapid glucocorticoid signaling via membrane-associated receptors. Endocrinology 147, 5549–5556 (2006).

    Article  CAS  PubMed  Google Scholar 

  202. Du, J. et al. Dynamic regulation of mitochondrial function by glucocorticoids. Proc. Natl Acad. Sci. USA 106, 3543–3548 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Psarra, A. M. & Sekeris, C. E. Glucocorticoid receptors and other nuclear transcription factors in mitochondria and possible functions. Biochim. Biophys. Acta 1787, 431–436 (2009). An important paper that shows translocation and actions of glucocorticoid receptors into mitochondria. This study illustrates the broadening of views of how glucocorticoids and other steroid hormones affect cellular functions.

    Article  CAS  PubMed  Google Scholar 

  204. Groeneweg, F. L., Karst, H., de Kloet, E. R. & Joels, M. Rapid non-genomic effects of corticosteroids and their role in the central stress response. J. Endocrinol. 209, 153–167 (2011).

    Article  CAS  PubMed  Google Scholar 

  205. Katona, I. & Freund, T. F. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nature Med. 14, 923–930 (2008).

    Article  CAS  PubMed  Google Scholar 

  206. Chavez, A. E., Chiu, C. Q. & Castillo, P. E. TRPV1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus. Nature Neurosci. 13, 1511–1518 (2010).

    Article  CAS  PubMed  Google Scholar 

  207. Hill, M. N. et al. Endogenous cannabinoid signaling is essential for stress adaptation. Proc. Natl Acad. Sci. USA 107, 9406–9411 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Di, S., Maxson, M. M., Franco, A. & Tasker, J. G. Glucocorticoids regulate glutamate and GABA synapse-specific retrograde transmission via divergent nongenomic signaling pathways. J. Neurosci. 29, 393–401 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Hill, M. N. et al. Functional interactions between stress and the endocannabinoid system: from synaptic signaling to behavioral output. J. Neurosci. 30, 14980–14986 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Raiteri, M., Angelini, F. & Levi, G. A simple apparatus for studying the release of neurotransmitters from synaptosomes. Eur. J. Pharmacol. 25, 411–414 (1974).

    Article  CAS  PubMed  Google Scholar 

  211. Raiteri, L. & Raiteri, M. Synaptosomes still viable after 25 years of superfusion. Neurochem. Res. 25, 1265–1274 (2000).

    Article  CAS  PubMed  Google Scholar 

  212. Bonanno, G. et al. Chronic antidepressants reduce depolarization-evoked glutamate release and protein interactions favoring formation of SNARE complex in hippocampus. J. Neurosci. 25, 3270–3279 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Joels, M. Corticosteroid effects in the brain: U-shape it. Trends Pharmacol. Sci. 27, 244–250 (2006).

    Article  CAS  PubMed  Google Scholar 

  214. Sapolsky, R. M. Stress, the Aging Brain and the Mechanisms of Neuron Death (MIT Press, 1992).

    Google Scholar 

  215. Conrad, C. D., LeDoux, J. E., Magarinos, A. M. & McEwen, B. S. Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav. Neurosci. 113, 902–913 (1999).

    Article  CAS  PubMed  Google Scholar 

  216. Radley, J. J. et al. Reversibility of apical dendritic retraction in the rat medial prefrontal cortex following repeated stress. Exp. Neurol. 196, 199–203 (2005).

    Article  PubMed  Google Scholar 

  217. Vyas, A., Pillai, A. G. & Chattarji, S. Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior. Neuroscience 128, 667–673 (2004).

    Article  CAS  PubMed  Google Scholar 

  218. Bloss, E. B., Janssen, W. G., McEwen, B. S. & Morrison, J. H. Interactive effects of stress and aging on structural plasticity in the prefrontal cortex. J. Neurosci. 30, 6726–6731 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Mitra, R., Jadhav, S., McEwen, B. S., Vyas, A. & Chattarji, S. Stress duration modulates the spatiotemporal patterns of spine formation in the basolateral amygdala. Proc. Natl Acad. Sci. USA 102, 9371–9376 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Mitra, R. & Sapolsky, R. M. Acute corticosterone treatment is sufficient to induce anxiety and amygdaloid dendritic hypertrophy. Proc. Natl Acad. Sci. USA 105, 5573–5578 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Magarinos, A. M. & McEwen, B. S. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors. Neuroscience 69, 89–98 (1995).

    Article  CAS  PubMed  Google Scholar 

  222. Reagan, L. P. et al. Chronic restraint stress up-regulates GLT-1 mRNA and protein expression in the rat hippocampus: reversal by tianeptine. Proc. Natl Acad. Sci. USA 101, 2179–2184 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Magarinos, A. M. et al. Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons. Hippocampus 21, 253–264 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Pawlak, R. et al. Tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus. Proc. Natl Acad. Sci. USA 102, 18201–18206 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Martin, K. P. & Wellman, C. L. NMDA receptor blockade alters stress-induced dendritic remodeling in medial prefrontal cortex. Cereb. Cortex 21, 2366–2373 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  226. Kim, K. et al. Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics. J. Cell. Physiol. 226, 2484–2493 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Bowden, C. L. et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch. Gen. Psychiatry 60, 392–400 (2003).

    Article  CAS  PubMed  Google Scholar 

  228. Brennan, B. P. et al. Rapid enhancement of glutamatergic neurotransmission in bipolar depression following treatment with riluzole. Neuropsychopharmacology 35, 834–846 (2010).

    Article  CAS  PubMed  Google Scholar 

  229. Gallagher, P. et al. Antiglucocorticoid treatments for mood disorders. Cochrane Database Syst. Rev. 21 Jan 2009 (doi:10.1002/14651858.CD005168.pub2).

  230. McLaughlin, R. J. & Gobbi, G. Cannabinoids and emotionality: a neuroanatomical perspective. Neuroscience 27 Jul 2011 (doi:10.1016/j.neuroscience.2011.07.052).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

M.P. is supported by the Italian Ministry of University and Research (MIUR-PRIN), the National Alliance for Research on Schizophrenia and Depression (NARSAD) and the European Union (FP6 — GENDEP Project). Z.Y. is supported by grants MH85774 and MH84233 from the US National Institute of Mental Health (NIMH). B.S.M. is supported by grant MH41256 from the NIMH, Conte Center grant 5 P50 MH58911 to J. Ledoux (principal investigator at New York University), and the MacArthur Foundation Research Network on Socioeconomic Status and Health. G.S. is supported by grants R01 MH081211 and 5 R01 MH071676-05 from the NIMH, the NARSAD, the National Center for Posttraumatic Stress Disorder of the US Department of Veterans Affairs, and the Clinical Neuroscience Division (West Haven, Connecticut) of the Department of Mental Health and Addiction Services for the State of Connecticut.

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Authors and Affiliations

  1. Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, Center of Neuropharmacology, University of Milan, Milan, 20133, Italy

    Maurizio Popoli

  2. Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, 14214, New York, USA

    Zhen Yan

  3. Laboratory of Neuroendocrinology, The Rockefeller University, New York, 10065, New York, USA

    Bruce S. McEwen

  4. Department of Psychiatry, Clinical Neuroscience Research Unit, Yale University School of Medicine, New Haven, 06511, Connecticut, USA

    Gerard Sanacora

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  1. Maurizio Popoli
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  2. Zhen Yan
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  4. Gerard Sanacora
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Correspondence to Gerard Sanacora.

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Competing interests

M.P. received support and/or has consulted for Abiogen, GlaxoSmithKline, MerckSharp and Dohme, Servier and Fidia. G.S. has received consulting fees from AstraZeneca, Avanier Pharmaceuticals, Bristol-Myers Squibb, Evotec, Eli Lilly & Co., Hoffman La-Roche, Johnson & Johnson, Novartis and Novum Pharmaceuticals over the past 24 months. He has also received additional grant support from AstraZeneca, Bristol-Myers Squibb, Hoffman La-Roche, Merck & Co. and Sepracor Inc. over the past 24 months. In addition, he is a co-inventor on a filed patent application by Yale University (PCTWO06108055A1). Z.Y. and B.S.M. report no competing financial interests.

Supplementary information

Supplementary information S1 (table)

Studies of glutamate release, glutamate transmission, glutamate receptors and glutamate clearance and metabolism in models of acute and chronic stress. (PDF 447 kb)

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Popoli, M., Yan, Z., McEwen, B. et al. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 13, 22–37 (2012). https://doi.org/10.1038/nrn3138

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