Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Stress and corticosterone increase the readily releasable pool of glutamate vesicles in synaptic terminals of prefrontal and frontal cortex

Molecular Psychiatry volume 19, pages 433–443 (2014)Cite this article

Subjects

Abstract

Stress and glucocorticoids alter glutamatergic transmission, and the outcome of stress may range from plasticity enhancing effects to noxious, maladaptive changes. We have previously demonstrated that acute stress rapidly increases glutamate release in prefrontal and frontal cortex via glucocorticoid receptor and accumulation of presynaptic SNARE complex. Here we compared the ex vivo effects of acute stress on glutamate release with those of in vitro application of corticosterone, to analyze whether acute effect of stress on glutamatergic transmission is mediated by local synaptic action of corticosterone. We found that acute stress increases both the readily releasable pool (RRP) of vesicles and depolarization-evoked glutamate release, while application in vitro of corticosterone rapidly increases the RRP, an effect dependent on synaptic receptors for the hormone, but does not induce glutamate release for up to 20 min. These findings indicate that corticosterone mediates the enhancement of glutamate release induced by acute stress, and the rapid non-genomic action of the hormone is necessary but not sufficient for this effect.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Popoli M, Yan Z, McEwen BS, Sanacora G . The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 2012; 13: 22–37.

    Article  CAS  Google Scholar 

  3. 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 

  4. 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 

  5. Musazzi L, Milanese M, Farisello P, Zappettini S, Tardito D, Barbiero VS et al. Acute stress increases depolarization-evoked glutamate release in the rat prefrontal/ frontal cortex: the dampening action of antidepressants. PLoS One 2010; 5: e8566.

    Article  Google Scholar 

  6. Joëls M, Sarabdjitsingh A, Karst H . Unraveling the time domains of corticosteroid hormone influences on brain activity: rapid, slow, and chronic modes. Pharmacol Rev 2012; 64: 901–938.

    Article  Google Scholar 

  7. Olijslagers JE, de Kloet ER, Elgersma Y, van Woerden GM, Joëls 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: 2542–2550.

    Article  CAS  Google Scholar 

  8. Yuen EY, Liu W, Karatsoreos IN, Ren Y, Feng J, McEwen BS et al. Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory. Mol Psychiatry 2011; 16: 156–170.

    Article  CAS  Google Scholar 

  9. Hill MN, McLaughlin RJ, Pan B, Fitzgerald ML, Roberts CJ, Lee TT et al. Recruitment of prefrontal cortical endocannabinoid signaling by glucocorticoids contributes to termination of the stress response. J Neurosci 2011; 31: 10506–10515.

    Article  CAS  Google Scholar 

  10. Tardito D, Milanese M, Bonifacino T, Musazzi L, Grilli M, Mallei A et al. Blockade of stress-induced increase of glutamate release in the rat prefrontal/frontal cortex by agomelatine involves synergy between melatonergic and 5-HT2C receptor-dependent pathways. BMC Neurosci 2010; 11: 68.

    Article  Google Scholar 

  11. Dunkley PR, Jarvie PE, Heath JW, Kidd GJ, Rostas JA . A rapid method for isolation of synaptosomes on Percoll gradients. Brain Res 1986; 372: 115–129.

    Article  CAS  Google Scholar 

  12. Stigliani S, Zappettini S, Raiteri L, Passalacqua M, Melloni E, Venturi C et al. Glia re-sealed particles freshly prepared from adult rat brain are competent for exocytotic release of glutamate. J Neurochem 2006; 96: 656–668.

    Article  CAS  Google Scholar 

  13. Raiteri M, Sala R, Fassio A, Rossetto O, Bonanno G . Entrapping of impermeant probes of different size into non permeabilized synaptosomes as a method to study presynaptic mechanisms. J Neurochem 2000; 74: 423–431.

    Article  CAS  Google Scholar 

  14. Longordo F, Feligioni M, Chiaramonte G, Sbaffi PF, Raiteri M, Pittaluga A . The human immunodeficiency virus-1 protein transactivator of transcription up-regulates N-methyl-D-aspartate receptor function by acting at metabotropic glutamate receptor 1 receptors coexisting on human and rat brain noradrenergic neurones. J Pharmacol Exp Ther 2006; 317: 1097–1105.

    Article  CAS  Google Scholar 

  15. Gardoni F, Picconi B, Ghiglieri V, Polli F, Bagetta V, Bernardi G et al. A critical interaction between NR2B and MAGUK in L-DOPA induced dyskinesia. J Neurosci 2006; 26: 2914–2922.

    Article  CAS  Google Scholar 

  16. Raiteri L, Raiteri M, Bonanno G . Coexistence and function of different neurotransmitter transporters in the plasma membrane of CNS neurons. Prog Neurobiol 2002; 68: 287–309.

    Article  CAS  Google Scholar 

  17. Milanese M, Zappettini S, Onofri F, Musazzi L, Tardito D, Bonifacino T et al. Abnormal exocytotic release of glutamate in a mouse model of amyotrophic lateral sclerosis. J Neurochem 2011; 116: 1028–1042.

    Article  CAS  Google Scholar 

  18. Van Eden CG, Uylings HB . Cytoarchitectonic development of the prefrontal cortex in the rat. J Comp Neurol 1985; 241: 253–267.

    Article  CAS  Google Scholar 

  19. Chen F, Madsen TM, Wegener G, Nyengaard JR . Imipramine treatment increases the number of hippocampal synapses and neurons in a genetic animal model of depression. Hippocampus 2010; 20: 1376–1384.

    Article  CAS  Google Scholar 

  20. Harris KM, Sultan P . Variation in the number, location and size of synaptic vesicles provides an anatomical basis for the non uniform probability of release at hippocampal CA1 synapses. Neuropharmacology 1995; 34: 1387–1395.

    Article  CAS  Google Scholar 

  21. Nava N, Chen F, Wegener G, Popoli M, Nyengaard JR . A new efficient method for synaptic vesicle quantification reveals differences between medial prefrontal cortex perforated and non-perforated synapses. J Comp Neurol 2014; 522: 284–297.

    Article  Google Scholar 

  22. Raiteri L, Stigliani S, Usai C, Diaspro A, Paluzzi S, Milanese M et al. Functional expression of release-regulating glycine transporters GLYT1 on GABAergic neurons and GLYT2 on astrocytes in mouse spinal cord. Neurochem Int 2008; 52: 103–112.

    Article  CAS  Google Scholar 

  23. Serulle Y, Sugimori M, Llinàs RR . Imaging synaptosomal calcium concentration microdomains and vesicle fusion by using total internal reflection fluorescent microscopy. Proc Natl Acad Sci USA 2007; 104: 1697–1702.

    Article  CAS  Google Scholar 

  24. Perego C, Cairano ES, Ballabio M, Magnaghi V . Neurosteroid allopregnanolone regulates EAAC1-mediated glutamate uptake and triggers actin changes in Schwann cells. J Cell Physiol 2012; 227: 1740–1751.

    Article  CAS  Google Scholar 

  25. D’amico A, Soragna A, Di Cairano E, Panzeri N, Anzai N, Vellea Sacchi F et al. The surface density of the glutamate transporter EAAC1 is controlled by interactions with PDZK1 and AP2 adaptor complexes. Traffic 2010; 11: 1455–1470.

    Article  Google Scholar 

  26. Zhou QG, Zhu LJ, Chen C, Wu HY, Luo CX, Chang L et al. Hippocampal neuronal nitric oxide synthase mediates the stress-related depressive behaviors of glucocorticoids by downregulating glucocorticoid receptor. J Neurosci 2011; 31: 7579–7590.

    Article  CAS  Google Scholar 

  27. Rosenmund C, Stevens CF . Definition of the readily releasable pool of vesicles at hippocampal synapses. Neuron 1996; 16: 1197–1207.

    Article  CAS  Google Scholar 

  28. Lonart G, Sudhof TC . Assembly of SNARE core complexes prior to neurotransmitter release sets the readily releasable pool of synaptic vesicles. J Biol Chem 2000; 275: 27703–27707.

    CAS  PubMed  Google Scholar 

  29. Fleck MW, Barrionuevo G, Palmer AM . Synaptosomal and vesicular accumulation of L-glutamate, L- aspartate and D- aspartate. Neurochem Int 2001; 39: 217–225.

    Article  CAS  Google Scholar 

  30. Wang L, Nadler JV . Reduced aspartate release from rat hippocampal synaptosomes loaded with clostridial toxin light chain by electroporation: evidence for an exocytotic mechanism. Neurosci Lett 2007; 412: 239–242.

    Article  CAS  Google Scholar 

  31. Raiteri L, Zappettini S, Milanese M, Fedele E, Raiteri M, Bonanno G . Mechanisms of glutamate release elicited in rat cerebrocortical nerve endings by ‘pathologically’ elevated extraterminal K+ concentrations. J Neurochem 2007; 103: 952–961.

    Article  CAS  Google Scholar 

  32. Bonanno G, Giambelli R, Raiteri L, Tiraboschi E, Zappettini S, Musazzi L et al. Chronic antidepressants reduce depolarization-evoked glutamate release and protein interactions favoring formation of SNARE complex in hippocampus. J Neurosci 2005; 25: 3270–3279.

    Article  CAS  Google Scholar 

  33. Prager EM, Brielmaier J, Bergstrom HC, McGuire J, Johnson LR . Localization of mineralocorticoid receptors at mammalian synapses. PLoS One 2010; 5: e14344.

    Article  CAS  Google Scholar 

  34. Zucker RS, Regehr WG . Short-term synaptic plasticity. Annu Rev Physiol 2002; 64: 355–405.

    Article  CAS  Google Scholar 

  35. Groves JT, Parthasarathy R, Forstner MB . Fluorescence imaging of membrane dynamics. Annu Rev Biomed Eng 2008; 10: 311–338.

    Article  CAS  Google Scholar 

  36. Sanacora G, Treccani G, Popoli M . Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 2012; 62: 63–77.

    Article  CAS  Google Scholar 

  37. Eagle AL, Knox D, Roberts MM, Mulo K, Liberzon I, Galloway MP et al. Single prolonged stress enhances hippocampal glucocorticoid receptor and phosphorylated protein kinase B levels. Neurosci Res 2012; 75: 130–137.

    Article  Google Scholar 

  38. Zhu LQ, Liu D, Hu J, Cheng J, Wang SH, Wang Q et al. GSK-3 beta inhibits presynaptic vesicle exocytosis by phosphorylating P/Q-type calcium channel and interrupting SNARE complex formation. J Neurosci 2010; 30: 3624–3633.

    Article  CAS  Google Scholar 

  39. Chandran A, Iyo AH, Jernigan CS, Legutko B, Austin MC, Karolewicz B . Reduced phosphorylation of the mTOR signaling pathway components in the amygdala of rats exposed to chronic stress. Prog Neuropsychopharmacol Biol Psychiatry 2013; 40: 240–245.

    Article  CAS  Google Scholar 

  40. Barbiero VS, Giambelli R, Musazzi L, Tiraboschi E, Tardito D, Perez J et al. Chronic antidepressants induce redistribution and differential activation of aCaM kinase II between presynaptic compartments. Neuropsychopharmacology 2007; 32: 2511–2519.

    Article  CAS  Google Scholar 

  41. Greengard P, Valtorta F, Czernik AJ, Benfenati F . Synaptic vesicle phosphoproteins and regulation of synaptic function. Science 1993; 259: 780–785.

    Article  CAS  Google Scholar 

  42. Sun J, Bronk P, Liu X, Han W, Südhof TC . Synapsins regulate use-dependent synaptic plasticity in the calyx of Held by a Ca2+/calmodulin-dependent pathway. Proc Natl Acad Sci USA 2006; 103: 2880–2885.

    Article  CAS  Google Scholar 

  43. Rosahl TW, Spillane D, Missler M, Herz J, Selig DK, Wolff JR et al. Essential functions of synapsins I and II in synaptic vesicle regulation. Nature 1995; 375: 488–493.

    Article  CAS  Google Scholar 

  44. Bloom O, Evergren E, Tomilin N, Kjaerulff O, Löw P, Brodin L et al. Colocalization of synapsin and actin during synaptic vesicle recycling. J Cell Biol 2003; 161: 737–747.

    Article  CAS  Google Scholar 

  45. Cesca F, Baldelli P, Valvolta F, Benfenati F . The synapsins: key actors of synapse function and plasticity. Prog Neurobiol 2010; 91: 313–348.

    Article  CAS  Google Scholar 

  46. 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 1997; 77: 65–73.

    Article  CAS  Google Scholar 

  47. Lowy M, Gault L, Yamamoto B . Adrenolectomy attenuates stress induced elevation in extracellular glutamate concentration in hippocampus. J Neurochem 1993; 61: 1957–1960.

    Article  CAS  Google Scholar 

  48. Reznikov LR, Grillo CA, Piroli GG, Pasumarthi RK, Reagan LP, Fadel J . Acute stress-mediated increases in extracellular glutamate levels in the rat amygdala: differential effects of antidepressant treatment. Eur J Neurosci 2007; 25: 3109–3114.

    Article  Google Scholar 

  49. 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 1999; 11: 2465–2473.

    Article  CAS  Google Scholar 

  50. Yuste R, Bonhoeffer T . Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu Rev Neurosci 2001; 24: 1071–1089.

    Article  CAS  Google Scholar 

  51. He LM, Zhang CG, Zhou Z, Xu T . Rapid inhibitory effects of corticosterone on calcium influx in rat dorsal root ganglion neurons. Neuroscience 2003; 116: 325–333.

    Article  CAS  Google Scholar 

  52. Huang CC, Yang DM, Lin CC, Kao LS . Involvement of Rab3A in vesicle priming during exocytosis: interaction with Munc13-1 and Munc18-1. Traffic 2011; 12: 1356–1370.

    Article  CAS  Google Scholar 

  53. Revest JM, Kaouane N, Mondin M, Le Roux A, Rougé-Pont F, Vallée M et al. The enhancement of stress-related memory by glucocorticoids depends on synapsin-Ia/Ib. Mol Psychiatry 2010; 15: 1140–1151.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from MIUR (PRIN 2009 prot.2009BRMW4W_001), Fondazione Cariplo Prog. 2011-0635, and from ECNP (ECNP Research Grant for Young Scientist 2010). GT was funded by the International PhD Program in Neuropharmacology, University of Catania. We thank Maurizio Abbate (Immagini & Computer, Italy) for helping with TIRF microscopy image processing. Centre for Stochastic Geometry and Advanced Bioimaging (Aarhus) is supported by Villum Foundation (Denmark). We thank Dr Fabrizio Gardoni for helping with TIF preparation.

Author information

Author notes

  1. G Treccani and L Musazzi: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Neuropsychopharmacology and Functional Neurogenomics–Dipartimento di Scienze Farmacologiche e Biomolecolari and CEND, Università di Milano, Milano, Italy

    G Treccani, L Musazzi, G Racagni & M Popoli

  2. Laboratory of Cell Physiology–Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milano, Italy

    C Perego

  3. Department of Pharmacy–Unit of Pharmacology and Toxicology, Center of Excellence for Biomedical Research, Università di Genova, Genova, Italy

    M Milanese, T Bonifacino & G Bonanno

  4. Stereology and Electron Microscopy Laboratory, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, Aarhus, Denmark

    N Nava & J R Nyengaard

  5. Department of Clinical Medicine, Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark,

    N Nava & G Wegener

  6. Neurobiology of Learning Unit, Scientific Institute San Raffaele and Università Vita e Salute San Raffaele, Milano, Italy

    J Lamanna & A Malgaroli

  7. Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Università di Catania, Catania, Italy

    F Drago

  8. IRCCS San Giovanni di Dio-Fatebenefratelli, Brescia, Italy

    G Racagni

  9. Centre of Excellence for Pharmaceutical Sciences, North West University, Potchefstroom, South Africa,

    G Wegener

Authors
  1. G Treccani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Musazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Perego
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Milanese
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N Nava
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T Bonifacino
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Lamanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Malgaroli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F Drago
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. G Racagni
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J R Nyengaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. G Wegener
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. G Bonanno
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M Popoli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Popoli.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Treccani, G., Musazzi, L., Perego, C. et al. Stress and corticosterone increase the readily releasable pool of glutamate vesicles in synaptic terminals of prefrontal and frontal cortex. Mol Psychiatry 19, 433–443 (2014). https://doi.org/10.1038/mp.2014.5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2014.5

Keywords

This article is cited by

Search

Advanced search

Quick links