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:

Impairment of synaptic plasticity by the stress mediator CRH involves selective destruction of thin dendritic spines via RhoA signaling

Abstract

Stress is ubiquitous in modern life and exerts profound effects on cognitive and emotional functions. Thus, whereas acute stress enhances memory, longer episodes exert negative effects through as yet unresolved mechanisms. We report a novel, hippocampus-intrinsic mechanism for the selective memory defects that are provoked by stress. CRH (corticotropin-releasing hormone), a peptide released from hippocampal neurons during stress, depressed synaptic transmission, blocked activity-induced polymerization of spine actin and impaired synaptic plasticity in adult hippocampal slices. Live, multiphoton imaging demonstrated a selective vulnerability of thin dendritic spines to this stress hormone, resulting in depletion of small, potentiation-ready excitatory synapses. The underlying molecular mechanisms required activation and signaling of the actin-regulating small GTPase, RhoA. These results implicate the selective loss of dendritic spine sub-populations as a novel structural and functional foundation for the clinically important effects of stress on cognitive and emotional processes.

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

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Joëls M, Baram TZ . The neuro-symphony of stress. Nat Rev Neurosci 2009; 6: 459–466.

    Article  Google Scholar 

  4. López JF, Akil H, Watson SJ . Neural circuits mediating stress. Biol Psychiatry 1999; 46: 1461–1471.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. McEwen BS . Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann NY Acad Sci 2004; 1032: 1–7.

    Article  Google Scholar 

  7. Clark L, Chamberlain SR, Sahakian BJ . Neurocognitive mechanisms in depression: implications for treatment. Annu Rev Neurosci 2009; 32: 57–74.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Fuchs E, Flugge G, Czeh B . Remodeling of neuronal networks by stress. Front Biosci 2006; 11: 2746–2758.

    Article  CAS  Google Scholar 

  10. Licinio J, Wong ML . Advances in depression research: 2011. Mol Psychiatry 2011; 16: 686–687.

    Article  CAS  Google Scholar 

  11. Radley JJ, Morrison JH . Repeated stress and structural plasticity in the brain. Ageing Res Rev 2005; 4: 271–287.

    Article  Google Scholar 

  12. Diamond DM, Campbell AM, Park CR, Woodson JC, Conrad CD, Bachstetter AD et al. Influence of predator stress on the consolidation versus retrieval of long-term spatial memory and hippocampal spinogenesis. Hippocampus 2006; 16: 571–576.

    Article  Google Scholar 

  13. Krugers HJ, Hoogenraad CC, Groc L . Stress hormones and AMPA receptor trafficking in synaptic plasticity and memory. Nat Rev Neurosci 2010; 11: 675–681.

    Article  CAS  Google Scholar 

  14. Segal M, Richter-Levin G, Maggio N . Stress-induced dynamic routing of hippocampal connectivity: a hypothesis. Hippocampus 2010; 12: 1332–1338.

    Article  Google Scholar 

  15. 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 

  16. Van Eekelen JA, Jiang W, De Kloet ER, Bohn MC . Distribution of the mineralocorticoid and the glucocorticoid receptor mRNAs in the rat hippocampus. J Neurosci Res 1988; 21: 88–94.

    Article  CAS  Google Scholar 

  17. Sánchez MM, Young LJ, Plotsky PM, Insel TR . Distribution of corticosteroid receptors in the rhesus brain: relative absence of glucocorticoid receptors in the hippocampal formation. J Neurosci 2000; 20: 4657–4668.

    Article  Google Scholar 

  18. Chen Y, Bender RA, Frotscher M, Baram TZ . Novel and transient populations of corticotropin-releasing hormone-expressing neurons in developing hippocampus suggest unique functional roles: a quantitative spatiotemporal analysis. J Neurosci 2001; 21: 7171–7181.

    Article  CAS  Google Scholar 

  19. Eichenbaum H, Yonelinas AP, Ranganath C . The medial temporal lobe and recognition memory. Annu Rev Neurosci 2007; 30: 123–152.

    Article  CAS  Google Scholar 

  20. Squire LR, Wixted JT, Clark RE . Recognition memory and the medial temporal lobe: a new perspective. Nat Rev Neurosci 2007; 8: 872–883.

    Article  CAS  Google Scholar 

  21. Colgin LL, Moser EI, Moser MB . Understanding memory through hippocampal remapping. Trends Neurosci 2008; 31: 469–477.

    Article  CAS  Google Scholar 

  22. Chen Y, Rex CS, Rice CJ, Dubé CM, Gall CM, Lynch G et al. Correlated memory defects and hippocampal dendritic spine loss after acute stress involve corticotropin-releasing hormone signaling. Proc Natl Acad Sci USA 2010; 29: 13123–13128.

    Article  Google Scholar 

  23. Woolley CS, Gould E, Frankfurt M, McEwen BS . Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J Neurosci 1990; 10: 4035–4039.

    Article  CAS  Google Scholar 

  24. Chen LY, Rex CS, Casale MS, Gall CM, Lynch G . Changes in synaptic morphology accompany actin signaling during LTP. J Neurosci 2007; 27: 5363–5372.

    Article  CAS  Google Scholar 

  25. Chen Y, Dubé CM, Rice CJ, Baram TZ . Rapid loss of dendritic spines after stress involves derangement of spine dynamics by corticotropin-releasing hormone. J Neurosci 2008; 28: 2903–2911.

    Article  CAS  Google Scholar 

  26. Chen Y, Brunson KL, Adelmann G, Bender RA, Frotscher M, Baram TZ . Hippocampal corticotropin releasing hormone: pre- and postsynaptic location and release by stress. Neuroscience 2004; 126: 533–540.

    Article  CAS  Google Scholar 

  27. Kramár EA, Chen LY, Brandon NJ, Rex CS, Liu F, Gall CM et al. Cytoskeletal changes underlie estrogen's acute effects on synaptic transmission and plasticity. J Neurosci 2009; 29: 12982–12993.

    Article  Google Scholar 

  28. Harris KM, Kater SB . Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function. Annu Rev Neurosci 1994; 17: 341–371.

    Article  CAS  Google Scholar 

  29. Hering H, Sheng M . Dendritic spines: structure, dynamics and regulation. Nat Rev Neurosci 2001; 2: 880–888.

    Article  CAS  Google Scholar 

  30. Bourne JN, Harris KM . Balancing structure and function at hippocampal dendritic spines. Annu Rev Neurosci 2008; 31: 47–67.

    Article  CAS  Google Scholar 

  31. Holtmaat A, Svoboda K . Experience-dependent structural synaptic plasticity in the mammalian brain. Nat Rev Neurosci 2009; 10: 647–658.

    Article  CAS  Google Scholar 

  32. Kasai H, Hayama T, Ishikawa M, Watanabe S, Yagishita S, Noguchi J . Learning rules and persistence of dendritic spines. Eur J Neurosci 2010; 32: 241–249.

    Article  Google Scholar 

  33. Rex CS, Chen LY, Sharma A, Liu J, Babayan AH, Gall CM et al. Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation. J Cell Biol 2009; 186: 85–97.

    Article  CAS  Google Scholar 

  34. Lin B, Kramár EA, Bi X, Brucher FA, Gall CM, Lynch G . Theta stimulation polymerizes actin in dendritic spines of hippocampus. J Neurosci 2005; 25: 2062–2069.

    Article  CAS  Google Scholar 

  35. Noam Y, Zha Q, Phan L, Wu RL, Chetkovich DM, Wadman WJ et al. Trafficking and surface expression of hyperpolarization-activated cyclic nucleotide-gated channels in hippocampal neurons. J Biol Chem 2010; 285: 14724–14736.

    Article  CAS  Google Scholar 

  36. Larson J, Wong D, Lynch G . Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation. Brain Res 1986; 368: 347–350.

    Article  CAS  Google Scholar 

  37. Halpain S . Actin and the agile spine: how and why do dendritic spines dance? Trends Neurosci 2000; 23: 141–146.

    Article  CAS  Google Scholar 

  38. Tada T, Sheng M . Molecular mechanisms of dendritic spine morphogenesis. Curr Opin Neurobiol 2006; 16: 95–101.

    Article  CAS  Google Scholar 

  39. Khan S, Milot M, Lecompte-Collin J, Plamondon H . Time-dependent changes in CRH concentrations and release in discrete brain regions following global ischemia: effects of MK-801 pretreatment. Brain Res 2004; 1016: 48–57.

    Article  CAS  Google Scholar 

  40. Tringali G, Lisi L, De Simone ML, Aubry JM, Preziosi P, Pozzoli G et al. Effects of olanzapine and quetiapine on corticotropin-releasing hormone release in the rat brain. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 1017–1021.

    Article  CAS  Google Scholar 

  41. 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 

  42. Fedulov V, Rex CS, Simmons DA, Palmer L, Gall CM, Lynch G . Evidence that long-term potentiation occurs within individual hippocampal synapses during learning. J Neurosci 2007; 27: 8031–8039.

    Article  CAS  Google Scholar 

  43. Segal M . Dendritic spines and long-term plasticity. Nat Neurosci 2005; 6: 277–284.

    Article  CAS  Google Scholar 

  44. Carroll RC, Beattie EC, von Zastrow M, Malenka RC . Role of AMPA receptor endocytosis in synaptic plasticity. Nat Rev Neurosci 2001; 2: 315–324.

    Article  CAS  Google Scholar 

  45. Boehm J, Kang MG, Johnson RC, Esteban J, Huganir RL, Malinow R . Synaptic incorporation of AMPA receptors during LTP is controlled by a PKC phosphorylation site on GluR1. Neuron 2006; 51: 213–225.

    Article  CAS  Google Scholar 

  46. Ehlers MD, Heine M, Groc L, Lee MC, Choquet D . Diffusional trapping of GluR1 AMPA receptors by input-specific synaptic activity. Neuron 2007; 54: 447–460.

    Article  CAS  Google Scholar 

  47. Makino H, Malinow R . AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis. Neuron 2009; 64: 381–390.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  49. Mitsushima D, Ishihara K, Sano A, Kessels HW, Takahashi T . Contextual learning requires synaptic AMPA receptor delivery in the hippocampus. Proc Natl Acad Sci USA 2011; 108: 12503–12508.

    Article  CAS  Google Scholar 

  50. Penzes P, Cahill ME, Jones KA, VanLeeuwen JE, Woolfrey KM . Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci 2011; 14: 285–293.

    Article  CAS  Google Scholar 

  51. McLaughlin KJ, Baran SE, Conrad CD . Chronic stress- and sex-specific neuromorphological and functional changes in limbic structures. Mol Neurobiol 2009; 40: 166–182.

    Article  CAS  Google Scholar 

  52. 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  Google Scholar 

  53. Liston C, Gan WB . Glucocorticoids are critical regulators of dendritic spine development and plasticity in vivo. Proc Natl Acad Sci USA 2011; 108: 16074–16079.

    Article  CAS  Google Scholar 

  54. Schmidt MV, Schlke JP, Liebl C, Stiess M, Avrabos C, Bock J et al. Tumor suppressor down-regulated in renal cell carcinoma 1 (DRR1) is a stress-induced actin bundling factor that modulates synaptic efficacy and cognition. Proc Natl Acad Sci USA 2011; 108: 17213–17218.

    Article  CAS  Google Scholar 

  55. Bale TL, Vale WW . CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol 2004; 44: 525–557.

    Article  CAS  Google Scholar 

  56. Yan XX, Toth Z, Schultz L, Ribak CE, Baram TZ . Corticotropin-releasing hormone (CRH)-containing neurons in the immature rat hippocampal formation: light and electron microscopic features and colocalization with glutamate decarboxylase and parvalbumin. Hippocampus 1998; 8: 231–243.

    Article  CAS  Google Scholar 

  57. Brunson KL, Chen Y, Avishai-Eliner S, Baram TZ . Stress and the developing hippocampus: a double-edged sword? Mol Neurobiol 2003; 27: 121–136.

    Article  CAS  Google Scholar 

  58. Radulovic J, Rühmann A, Liepold T, Spiess J . Modulation of learning and anxiety by corticotropin-releasing factor (CRF) and stress: differential roles of CRF receptors 1 and 2. J Neurosci 1999; 19: 5016–5025.

    Article  CAS  Google Scholar 

  59. Blank T, Nijholt I, Eckart K, Spiess J . Priming of long-term potentiation in mouse hippocampus by corticotropin-releasing factor and acute stress: implications for hippocampus-dependent learning. J Neurosci 2002; 22: 3788–3794.

    Article  CAS  Google Scholar 

  60. Refojo D, Schweizer M, Kuehne C, Ehrenberg S, Thoeringer C, Vogl AM et al. Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. Science 2011; 333: 1903–1907.

    Article  CAS  Google Scholar 

  61. Behan DP, Heinrichs SC, Troncoso JC, Liu XJ, Kawas CH, Ling N et al. Displacement of corticotropin-releasing factor from its binding protein as a possible treatment for Alzheimer's disease. Nature 1995; 378: 284–287.

    Article  CAS  Google Scholar 

  62. Wang XD, Chen Y, Wolf M, Wagner KV, Liebl C, Scharf SH et al. Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling. Neurobiol Dis 2011; 42: 300–310.

    Article  CAS  Google Scholar 

  63. Ivy AS, Rex CS, Chen Y, Dubé C, Maras PM, Grigoriadis DE et al. Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors. J Neurosci 2010; 30: 13005–13015.

    Article  CAS  Google Scholar 

  64. Penzes P, Jones KA . Dendritic spine dynamics--a key role for kalirin-7. Trends Neurosci 2008; 31: 419–427.

    Article  CAS  Google Scholar 

  65. Kang MG, Guo Y, Huganir RL . AMPA receptor and GEF-H11 Lf complex regulates dendritic spine development through RhoA signaling cascade. Proc Natl Acad Sci USA 2009; 106: 3549–3554.

    Article  CAS  Google Scholar 

  66. Ryan XP, Alldritt J, Svenningsson P, Allen PB, Wu GY, Nairn AC et al. The Rho-specific GEF Lfc interacts with neurabin and spinophilin to regulate dendritic spine morphology. Neuron 2005; 47: 85–100.

    Article  CAS  Google Scholar 

  67. Sfakianos MK, Eisman A, Gourley SL, Bradley WD, Scheetz AJ, Settleman J et al. Inhibition of Rho via Arg and p190RhoGAP in the postnatal mouse hippocampus regulates dendritic spine maturation, synapse and dendrite stability, and behavior. J Neurosci 2007; 27: 10982–10992.

    Article  CAS  Google Scholar 

  68. Roozendaal B, Brunson KL, Holloway BL, McGaugh JL, Baram TZ . Involvement of stress-released corticotropin-releasing hormone in the basolateral amygdala in regulating memory consolidation. Proc Natl Acad Sci USA 2002; 99: 13908–13913.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by NIH Grants NS28912, MH73136 (to TZB) and P01 NS45260 (to CMG, GL and TZB) and fellowship MH083396 (to LYC). We thank Barbara Cartwright for editorial help.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Y Chen or T Z Baram.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, Y., Kramár, E., Chen, L. et al. Impairment of synaptic plasticity by the stress mediator CRH involves selective destruction of thin dendritic spines via RhoA signaling. Mol Psychiatry 18, 485–496 (2013). https://doi.org/10.1038/mp.2012.17

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2012.17

Keywords

This article is cited by

Search

Quick links