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Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility

Molecular Psychiatry volume 20, pages 755–763 (2015)Cite this article

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Abstract

Why do some individuals succumb to stress and develop debilitating psychiatric disorders, whereas others adapt well in the face of adversity? There is a gap in understanding the neural bases of individual differences in the responses to environmental factors on brain development and functions. Here, using a novel approach for screening an inbred population of laboratory animals, we identified two subpopulations of mice: susceptible mice that show mood-related abnormalities compared with resilient mice, which cope better with stress. This approach combined with molecular and behavioral analyses, led us to recognize, in hippocampus, presynaptic mGlu2 receptors, which inhibit glutamate release, as a stress-sensitive marker of individual differences to stress-induced mood disorders. Indeed, genetic mGlu2 deletion in mice results in a more severe susceptibility to stress, mimicking the susceptible mouse sub-population. Furthermore, we describe an underlying mechanism by which glucocorticoids, acting via mineralocorticoid receptors (MRs), decrease resilience to stress via downregulation of mGlu2 receptors. We also provide a mechanistic link between MRs and an epigenetic control of the glutamatergic synapse that underlies susceptibility to stressful experiences. The approach and the epigenetic allostasis concept introduced here serve as a model for identifying individual differences based upon biomarkers and underlying mechanisms and also provide molecular features that may be useful in translation to human behavior and psychopathology.

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References

  1. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien S, Ballestar ML et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 2005; 102: 10604–10609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Freund J, Brandmaier AM, Lewejohann L, Kirste I, Kritzlerm M, Kruger A . Emergence of individuality in genetically identical mice. Science 2013; 340: 756–759.

    Article  CAS  PubMed  Google Scholar 

  3. Cavigelli SA, McClintock MK . Fear of novelty in infant rats predicts adult corticosterone dynamics and an early death. Proc Natl Acad Sci USA 2003; 100: 16131–16136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Miller MM, Morrison JH, McEwen BS . Basal anxiety-like behavior predicts differences in dendritic morphology in the medial prefrontal cortex in two strains of rats. Behav Brain Res 2012; 229: 280–288.

    Article  PubMed  Google Scholar 

  5. Southwick SM, Charney DS . The science of resilience: implications for the prevention and treatment of depression. Science 2012; 338: 79–82.

    Article  CAS  PubMed  Google Scholar 

  6. Wood SK, Walker HE, Valentino RJ, Bhatnagar S . Individual differences in reactivity to social stress predict susceptibility and resilience to a depressive phenotype: role of corticotropin-releasing factor. Endocrinology 2010; 151: 1795–1805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. McEwen BS . Brain on stress: how the social environment gets under the skin. Proc Natl Acad Sci USA 2012; 109: 17180–17185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Machado-Vieira R, Soeiro-De-Souza MG, Richards EM, Teixeira AL, Zarate CA Jr . Multiple levels of impaired neural plasticity and cellular resilience in bipolar disorder: developing treatments using an integrated translational approach. World J Biol Psychiatry 2013; 15: 84–95.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Zovkic IB, Meadows JP, Kaas GA, Sweatt JD . Interindividual variability in stress susceptibility: a role for epigenetic mechanisms in PTSD. Front Psychiatry 2013; 4: 60.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Charney DS . Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress. Am J Psychiatry 2004; 161: 195–216.

    Article  PubMed  Google Scholar 

  11. Yehuda R, Flory JD, Southwick S, Charney DS . Developing an agenda for translational studies of resilience and vulnerability following trauma exposure. Ann NY Acad Sci 2006; 1071: 379–396.

    Article  PubMed  Google Scholar 

  12. Feder A, Nestler EJ, Charney DS . Psychobiology and molecular genetics of resilience. Nat Rev Neurosci 2009; 10: 446–457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kinnally EL, Mann JJ . Early life stress programming and suicide risk. Psychiatr Ann 2012; 42: 95–100.

    Article  Google Scholar 

  14. Oquendo MA, Brent DA, Birmaher B, Greenhill L, Kolko D, Stanley B et al. Posttraumatic stress disorder comorbid with major depression: factors mediating the association with suicidal behavior. Am J Psychiatry 2005; 162: 560–566.

    Article  PubMed  Google Scholar 

  15. Popoli M, Yan Z, McEwen BS, Sanacora G . The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 2011; 13: 22–37.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Nasca C, Xenos D, Barone Y, Caruso A, Scaccianoce S, Matrisciano F et al. L- acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors. Proc Natl Acad Sci USA 2013; 110: 4804–4809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kim JS, Schmid-Burgk W, Claus D, Kornhuber HH . Increased serum glutamate in depressed patients. Arch Psychiatr Nervenkr 1982; 232: 299–304.

    Article  CAS  PubMed  Google Scholar 

  18. Mitani H . Correlation between plasma levels of glutamate, alanine and serine with severity of depression. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 1155–1158.

    Article  CAS  PubMed  Google Scholar 

  19. 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 2007; 11: 2465–2473.

    Article  Google Scholar 

  20. Overstreet DH . The Flinders sensitive line rats: a genetic animal model of depression. Neurosci Biobehav Rev 1993; 17: 51–68.

    Article  CAS  PubMed  Google Scholar 

  21. Flight MH . Antidepressant epigenetic action. Nat Rev Neurosci 2013; 14: 226.

    Article  PubMed  Google Scholar 

  22. Russo SJ, Charney DS . Next generation antidepressants. Proc Natl Acad Sci USA 2013; 110: 4441–4442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. Yuen EY, Wei J, Liu W, Zhong P, Li X, Yan Z . Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex. Neuron 2012; 73: 962–977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Liston C, Gan WB . Glucocorticoids are critical regulators of dendritic spine development and plasticity in vivo. Proc Natl Acad Sci USA 2011; 38: 16074–16079.

    Article  Google Scholar 

  26. Nasca C, Orlando R, Marchiafava M, Boldrini P, Battaglia G, Scaccianoce S et al. Exposure to predator odor and resulting anxiety enhances the expression of the α2 δ subunit of voltage-sensitive calcium channels in the amygdala. J Neurochem 2013; 125: 649–656.

    Article  CAS  PubMed  Google Scholar 

  27. Nestler EJ, Hyman SE . Animal models of neuropsychiatric disorders. Nat Neurosci 2010; 13: 1161–1169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. McEwen BS . Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism 2005; 54: 20–23.

    Article  CAS  PubMed  Google Scholar 

  29. Myers B, McKlveen JM, Herman JP . Glucocorticoid actions on synapses, circuits, and behavior: Implications for the energetics of stress. Front Neuroendocrinol 2014; 35: 180–196.

    Article  CAS  PubMed  Google Scholar 

  30. Groeneweg FL, Karst H, de Kloet ER, Joëls M . Rapid non-genomic effects of corticosteroids and their role in the central stress response. J Endocrinol 2011; 2: 153–167.

    Article  Google Scholar 

  31. 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  PubMed  PubMed Central  Google Scholar 

  32. McEwen BS, Morrison JH . The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron 2013; 79: 16–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Russo SJ, Murrough JW, Han MH, Charney DS, Nestler EJ . Neurobiology of resilience. Nat Neurosci 2012; 15: 1475–1484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Herman JP, Cullinan WE . Neurocircuitry of stress: central control of the hypothalamo- pituitary-adrenocortical axis. Trends Neurosci 1997; 20: 78–84.

    Article  CAS  PubMed  Google Scholar 

  35. Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 2007; 131: 391–404.

    Article  CAS  PubMed  Google Scholar 

  36. Gunduz-Cinar O, Hill MN, McEwen BS, Holmes A . Amygdala FAAH and anandamide: mediating protection and recovery from stress. Trends Pharmacol Sci 2013; 34: 637–644.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Brydges NM, Jin R, Seckl J, Holmes MC, Drake AJ, Hall J .. Juvenile stress enhances anxiety and alters corticosteroid receptor expression in adulthood. Brain Behav 2014; 1: 4–13.

    Article  Google Scholar 

  38. Tang AC, Reeb-Sutherland BC, Romeo RD, McEwen BS . On the causes of early life experience effects: evaluating the role of mom. Front Neuroendocrinol 2014; 35: 245–251.

    Article  PubMed  Google Scholar 

  39. Meaney MJ, Szyf M . Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome. Dialogues Clin Neurosci 2005; 7: 103–123.

    PubMed  PubMed Central  Google Scholar 

  40. Parker KJ, Buckmaster CL, Schatzberg AF, Lyons DM . Prospective investigation of stress innoculation in young monkeys. Arch Gen Psychiat 2004; 61: 933–941.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  42. Haller J, Mikics E, Makara GB . The effects of non-genomic glucocorticoid mechanisms on bodily functions and the central neural system. A critical evaluation of findings. Front Neuroendocrinol 2007; 29: 273–291.

    Article  PubMed  Google Scholar 

  43. Swanson CJ, Bures M, Johnson MP, Linden AM, Monn JA, Schoepp DD . Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov 2005; 4: 131–144.

    Article  CAS  PubMed  Google Scholar 

  44. Timmermans W, Xiong H, Hoogenraad CC, Krugers HJ . Stress and excitatory synapses: from health to disease. Neuroscience 2013; 248: 626–636.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by AFSP, HDRF and NIH Grant RO1 MH41256. We thank the ACNP (American Congress of Neuropsychopharmacology) and ECNP (European Congress of Neuropsychopharmacology) for awarding the preliminary results of this research. mGlu2 receptor-knockout mice (mGlu2−/− mice) were kindly provided by S. Nakanishi, University of Kyoto, Kyoto, Japan.

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Authors and Affiliations

  1. Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA

    C Nasca, D Zelli & B S McEwen

  2. Department Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy

    C Nasca & F Nicoletti

  3. The Rockefeller University, Center for Clinical and Translational Science, New York, NY, USA

    B Bigio

  4. Istituto di Ricovero e Cura a Carattere Scientifico Neuromed, Pozzilli, Italy

    F Nicoletti

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  1. C Nasca
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Correspondence to C Nasca or B S McEwen.

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Nasca, C., Bigio, B., Zelli, D. et al. Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility. Mol Psychiatry 20, 755–763 (2015). https://doi.org/10.1038/mp.2014.96

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