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Glucocorticoid Receptors are Localized to Dendritic Spines and Influence Local Actin Signaling

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Abstract

Glucocorticoids affect learning and memory but the cellular mechanisms involved are poorly understood. The present studies tested if the stress-responsive glucocorticoid receptor (GR) is present and regulated within dendritic spines, and influences local signaling to the actin cytoskeleton. In hippocampal field CA1, 13 % of synapses contained GR-immunoreactivity. Three-dimensional reconstructions of CA1 dendrites showed that GR aggregates are present in both spine heads and necks. Consonant with evidence that GRα mRNA associates with the translation regulator Fragile X Mental Retardation Protein (FMRP), spine GR levels were rapidly increased by group 1 mGluR activation and reduced in mice lacking FMRP. Treatment of cultured hippocampal slices with the GR agonist dexamethasone rapidly (15–30 min) increased total levels of phosphorylated (p) Cofilin and extracellular signal-regulated kinase (ERK) 1/2, proteins that regulate actin polymerization and stability. Dexamethasone treatment of adult hippocampal slices also increased numbers of PSD95+ spines containing pERK1/2, but reduced numbers of pCofilin-immunoreactive spines. Dexamethasone-induced increases in synaptic pERK1/2 were blocked by the GR antagonist RU-486. These results demonstrate that GRs are present in hippocampal spines where they mediate acute glucocorticoid effects on local spine signaling. Through effects on these actin regulatory pathways, GRs are positioned to exert acute effects on synaptic plasticity.

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References

  1. Romeo RD, Waters EM, McEwen BS (2004) Steroid-induced hippocampal synaptic plasticity: sex differences and similarities. Neuron Glia Biol 1:219–229

    Article  PubMed  Google Scholar 

  2. Tata DA, Anderson BJ (2010) The effects of chronic glucocorticoid exposure on dendritic length, synapse numbers and glial volume in animal models: implications for hippocampal volume reductions in depression. Physiol Behav 99:186–193

    Article  PubMed  CAS  Google Scholar 

  3. Chaouloff F, Groc L (2011) Temporal modulation of hippocampal excitatory transmission by corticosteroids and stress. Front Neuroendocrinol 32:25–42

    Article  PubMed  CAS  Google Scholar 

  4. Haller J, Mikics E, Makara GB (2008) 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

    Article  PubMed  CAS  Google Scholar 

  5. Evanson NK, Herman J, P., Sakai RR, Krause EG (2010) Nongenomic actions of adrenal steroids in the central nervous system. J Neuroendocrinol. 846–861

  6. Ffrench-Mullen JM (1995) Cortisol inhibition of calcium currents in guinea pig hippocampal CA1 neurons via G-protein-coupled activation of protein kinase C. J Neurosci 15:903–911

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  8. Qi AQ, Qiu J, Xiao L, Chen YZ (2005) Rapid activation of JNK and p38 by glucocorticoids in primary cultured hippocampal cells. J Neurosci Res 80:510–517

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  10. Johnson LR, Farb C, Morrison JH, McEwen BS, LeDoux JE (2005) Localization of glucocorticoid receptors at postsynaptic membranes in the lateral amygdala. Neuroscience 136:289–299

    Article  PubMed  CAS  Google Scholar 

  11. Komatsuzaki Y, Murakami G, Tsurugizawa T, Mukai H, Tanabe N, Mitsuhashi K, Kawata M, Kimoto T, Ooishi Y, Kawato S (2005) Rapid spinogenesis of pyramidal neurons induced by activation of glucocorticoid receptors in adult male rat hippocampus. Biochem Biophys Res Commun 335:1002–1007

    Article  PubMed  CAS  Google Scholar 

  12. Miyashiro KY, Beckel-Mitchener A, Purk TP, Becker KG, Barret T, Liu L, Carbonetto S, Weiler IJ, Greenough WT, Eberwine J (2003) RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice. Neuron 37:417–431

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  14. Pavlides C, Watanabe Y, Magariños AM, McEwen BS (1995) Opposing roles of type I and type II adrenal steroid receptors in hippocampal long-term potentiation. Neuroscience 68:387–394

    Article  PubMed  CAS  Google Scholar 

  15. Alfarez DN, Wiegert O, Joëls M, Krugers HJ (2002) Corticosterone and stress reduce synaptic potentiation in mouse hippocampal slices with mild stimulation. Neuroscience 115:1119–1126

    Article  PubMed  CAS  Google Scholar 

  16. Maggio N, Segal M (2007) Striking variations in corticosteroid modulation of long-term potentiation along the septotemporal axis of the hippocampus. J Neurosci 27:5757–5765

    Article  PubMed  CAS  Google Scholar 

  17. Wiegert O, Pu Z, Shor S, Joëls M, Krugers HJ (2005) Glucocorticoid receptor activation selectively hampers N-methyl-D-aspartate receptor dependent hippocampal synaptic plasticity in vitro. Neuroscience 135:403–411

    Article  PubMed  CAS  Google Scholar 

  18. Lynch G, Rex CS, Chen LY, Gall CM (2008) The substrates of memory: defects, treatments, and enhancement. Eur J Pharmacol 585:2–13

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  20. Krucker T, Siggins GR, Halpain S (2000) Dynamic actin filaments are required for stable long-term potentiation (LTP) in area CA1 of the hippocampus. Proc Natl Acad Sci USA 97:6856–6861

    Article  PubMed  CAS  Google Scholar 

  21. Ransom RF, Lam NG, Hallett MA, Atkinson SJ, Smoyer WE (2005) Glucocorticoids protect and enhance recovery of cultured murine podocytes via actin filament stabilization. Kidney Int 68:2473–2483

    Article  PubMed  CAS  Google Scholar 

  22. Rubenstein NM, Callahan JA, Lo DH, Firestone GL (2007) Selective glucocorticoid control of Rho kinase isoforms regulate cell-cell interactions. Biochem Biophys Res Commun 354:603–607

    Article  PubMed  CAS  Google Scholar 

  23. Filla MS, Schwinn MK, Nosie AK, Clark RW, Peters DM (2011) Dexamethasone-associated cross-linked actin network formation in human trabecular meshwork cells involves β3 integrin signaling. Invest Ophthalmol Vis Sci 52:2952–2959

    Article  PubMed  CAS  Google Scholar 

  24. Bakker CE, Verheij C, Willemsen R, Vanderhelm R, Oerlemans F, Vermey M, Bygrave A, Hoogeveen AT, Oostra BA, Reyniers E, Deboulle K, Dhooge R, Cras P, Vanvelzen D, Nagels G, Martin JJ, Dedyn PP, Darby JK, Willems PJ, Consortium TD-BFX (1994) Fmr1 knockout mice: a model to study fragile x mental retardation. The Dutch-Belgium Fragile X Consortium. Cell 78:23–33

    Google Scholar 

  25. Feng G, Mellor RH, Bernstein M, Keller-Peck C, Nguyen QT, Wallace M, Nerbonne JM, Lichtman JW, Sanes JR (2000) Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28:41–51

    Article  PubMed  CAS  Google Scholar 

  26. D’Agostino J, Vaeth GF, Henning SJ (1982) Diurnal rhythm of total and free concentrations of serum corticosterone in the rat. Acta Endocrinol (Copenh) 100:85–90

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  28. Sarabdjitsingh RA, Meijer OC, de Kloet ER (2010) Specificity of glucocorticoid receptor primary antibodies for analysis of receptor localization patterns in cultured cells in hippocampus. Brain Res 1331:1–11

    Article  PubMed  CAS  Google Scholar 

  29. Bickel PE, Scherer PE, Schnitzer JE, Oh P, Lisanti MP, Lodish HF (1997) Flotillin and epidermal surface antigen define a new family of caveolae-associated integral membrane proteins. J Biol Chem 272:13793–13802

    Article  PubMed  CAS  Google Scholar 

  30. Chen LY, Rex CS, Babayan AH, Kramár EA, Lynch G, Gall CM, Lauterborn JC (2010) Physiological activation of synaptic Rac> PAK (p-21 activated kinase) signaling is defective in a mouse model of fragile X syndrome. J Neurosci 30:10977–10984

    Article  PubMed  CAS  Google Scholar 

  31. Chen L, Rex C, Sanaiha Y, Lynch G, Gall C (2010) Learning induces neurotrophin signaling at hippocampal synapses. Proc Natl Acad Sci USA 107:7030–7035

    Article  PubMed  CAS  Google Scholar 

  32. Chen LY, Rex CS, Pham DT, Lynch G, Gall CM (2010) BDNF signaling during learning is regionally differentiated within hippocampus. J Neurosci 30:15097–15101

    Article  PubMed  CAS  Google Scholar 

  33. Rex CS, Gavin CF, Rubio MD, Kramar EA, Chen LY, Jia Y, Huganir RL, Muzyczka N, Gall CM, Miller CA, Lynch G, Rumbaugh G (2010) Myosin IIb regulates actin dynamics during synaptic plasticity and memory formation. Neuron 67:603–617

    Article  PubMed  CAS  Google Scholar 

  34. Lauterborn JC, Pineda EA, Chen LY, Ramirez EA, Lynch G, Gall CM (2009) Ampakines cause sustained increases in brain-derived neurotrophic factor signaling at excitatory synapses without changes in AMPA receptor subunit expression. Neuroscience 159:283–295

    Article  PubMed  CAS  Google Scholar 

  35. Morales-Medina JC, Sanchez F, Flores G, Dumont Y, Quirion R (2009) Morphological reorganization after repeated corticosterone administration in the hippocampus, nucleus accumbens and amygdala in the rat. J Chem Neuroanat 38:266–272

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  38. Joëls M, Krugers HJ (2007) LTP after stress: up or down? Neural Plast 2007:93202–93208

    Article  PubMed  Google Scholar 

  39. Bernard-Trifilo JA, Kramár EA, Torp R, Lin CY, Pineda EA, Lynch G, Gall CM (2005) Integrin signaling cascades are operational in adult hippocampal synapses and modulate NMDA receptor physiology. J Neurochem 93:834–849

    Article  PubMed  CAS  Google Scholar 

  40. Megías M, Emri Z, Freund TF, Gulyás AI (2001) Total number and distribution of inhibitory and excitatory synapses on hippocampal CA1 pyramidal cells. Neuroscience 102:527–540

    Article  PubMed  Google Scholar 

  41. Aoki C, Miko I, Oviedo H, Mikeladze-Dvali T, Alexandre L, Sweeney N, Bredt DS (2001) Electron microscopic immunocytochemical detection of PSD-95, PSD-93, SAP-102, and SAP-97 at postsynaptic, presynaptic, and nonsynaptic sites of adult and neonatal rat visual cortex. Synapse 40:239–257

    Article  PubMed  CAS  Google Scholar 

  42. Hunt C, Schenker L, Kennedy M (1996) PSD-95 is associated with the postsynaptic density and not with the presynaptic membrane at forebrain synapses. J Neurosci 16:1380–1388

    PubMed  CAS  Google Scholar 

  43. Sans N, Petralia R, Wang Y, Jn B, Hell J, Wenthold R (2000) A developmental change in NMDA receptor-associated proteins at hippocampal synapses. J Neurosci 20:1260–1271

    PubMed  CAS  Google Scholar 

  44. Ronesi JA, Huber KM (2008) Metabotropic glutamate receptors and fragile x mental retardation protein: partners in translational regulation at the synapse. Sci Signal 1:pe6

    Article  PubMed  Google Scholar 

  45. Dictenberg JB, Swanger SA, Antar LN, Singer RH, Bassell GJ (2008) A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome. Dev Cell 14:926–939

    Article  PubMed  CAS  Google Scholar 

  46. Kao DI, Aldridge GM, Weiler IJ, Greenough WT (2010) Altered mRNA transport, docking, and protein translation in neurons lacking fragile X mental retardation protein. Proc Natl Acad Sci USA 107:15601–15606

    Article  PubMed  CAS  Google Scholar 

  47. Todd PK, Mack KJ, Malter JS (2003) The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95. Proc Natl Acad Sci USA 100:14374–14378

    Article  PubMed  CAS  Google Scholar 

  48. Kramár EA, Lin B, Rex CS, Gall CM, Lynch G (2006) Integrin-driven actin polymerization consolidates long-term potentiation. Proc Natl Acad Sci USA 103:5579–5584

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  50. Bamburg JR, McGough A, Ono S (1999) Putting a new twist on actin: ADF/cofilins modulate actin dynamics. Trends Cell Biol 9:364–370

    Article  PubMed  CAS  Google Scholar 

  51. Martinez-Quiles N, Ho HY, Kirschner MW, Ramesh N, Geha RS (2004) Erk/Src phosphorylation of cortactin acts as a switch on-switch off mechanism that controls its ability to activate N-WASP. Mol Cell Biol 24:5269–5280

    Article  PubMed  CAS  Google Scholar 

  52. Mullins RD, Heuser JA, Pollard TD (1998) The interaction of Arp2/3 complex with actin: nucleation, high affinity pointed end capping, and formation of branching networks of filaments. Proc Natl Acad Sci USA 95:6181–6186

    Article  PubMed  CAS  Google Scholar 

  53. Weaver AM, Karginov AV, Kinley AW, Weed SA, Li Y, Parsons JT, Cooper JA (2001) Cortactin promotes and stabilizes Arp2/3-induced actin filament network formation. Curr Biol 11:370–374

    Article  PubMed  CAS  Google Scholar 

  54. Wang YF, Hatton GI (2007) Interaction of extracellular signal-regulated protein kinase 1/2 with actin cytoskeleton in supraoptic oxytocin neurons and astrocytes: role in burst firing. J Neurosci 27:13822–13834

    Article  PubMed  CAS  Google Scholar 

  55. Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84:87–136

    Article  PubMed  CAS  Google Scholar 

  56. Alonso M, Medina JH, Pozzo-Miller L (2004) ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. Learn Mem 11:172–178

    Article  PubMed  Google Scholar 

  57. Olijslagers JE, de Kloet ER, Elgersma Y, van Woerden GM, Joëls M, Karst H (2008) Rapid changes in hippocampal CA1 pyramidal cell function via pre- as well as postsynaptic membrane mineralocorticoid receptors. Eur J Neurosci 27:2542–2550

    Article  PubMed  CAS  Google Scholar 

  58. Hill MN, McEwen BS (2009) Endocannabinoids: The silent partner of glucocorticoids in the synapse. Proc Natl Acad Sci USA 106:4579–4580

    Article  PubMed  CAS  Google Scholar 

  59. Barsegyan A, Mackenzie SM, Kurose BD, McGaugh JL, Roozendaal B (2010) Glucocorticoids in the prefrontal cortex enhance memory consolidation and impair working memory by a common neural mechanism. Proc Natl Acad Sci USA 107:16655–16660

    Article  PubMed  CAS  Google Scholar 

  60. Schmidt KL, Malisch JL, Breuner CW, Soma KK (2010) Corticosterone and cortisol binding sites in plasma, immune organs and brain of developing zebra finches: intracellular and membrane-associated receptors. Brain Behav Immun 24:908–918

    Article  PubMed  CAS  Google Scholar 

  61. Weiler IJ, Greenough WT (1993) Metabotropic glutamate receptors trigger postsynaptic protein synthesis. Proc Natl Acad Sci USA 90:7168–7171

    Article  PubMed  CAS  Google Scholar 

  62. Woolley CA, Gould E, McEwen BS (1990) Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res 531:225–231

    Article  PubMed  CAS  Google Scholar 

  63. Magarinos AM, McEwen BS (1995) Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: comparison of stressors. Neuroscience 69:83–88

    Article  PubMed  CAS  Google Scholar 

  64. Sousa N, Paula-Barbosa MM, Almeida OF (1999) Ligand and subfield specificity of corticoid-induced neuronal loss in the rat hippocampal formation. Neuroscience 89:1079–1087

    Article  PubMed  CAS  Google Scholar 

  65. Yang CH, Huang CC, Hsu KS (2004) Behavioral stress modifies hippocampal synaptic plasticity through corticosterone-induced sustained extracellular signal-regulated kinase/mitogen-activated protein kinase activation. J Neurosci 24:11029–11034

    Article  PubMed  CAS  Google Scholar 

  66. Lee SY, Kang JS, Song GY, Myung CS (2006) Stress induces the expression of heterotrimeric G protein beta subunits and the phosphorylation of PKB/Akt and ERK1/2 in rat brain. Neurosci Res 56:180–192

    Article  PubMed  CAS  Google Scholar 

  67. Munhoz CD, Sorrells SF, Caso JR, Scavone C, Sapolsky RM (2010) Glucocorticoids exacerbate lipopolysaccharide-induced signaling in the frontal cortex and hippocampus in a dose-dependent manner. J Neurosci 30:13690–13698

    Article  PubMed  CAS  Google Scholar 

  68. Kramár EA, Chen LY, Brandon NJ, Rex CS, Liu F, Gall CM, Lynch G (2009) Cytoskeletal changes underlie estrogen’s acute effects on synaptic transmission and plasticity. J Neurosci 29:12982–12993

    Article  PubMed  Google Scholar 

  69. Kramár E, Chen L, Lauterborn J, Simmons D, Gall C, Lynch G (2010) BDNF and BDNF upregulation restores synaptic plasticity in middle-aged ovariectomized rats in Society for Neuroscience. 2010 Neuroscience Meeting Planner, San Diego

    Google Scholar 

  70. Rüegg J, Holsboer F, Turck C, Rein T (2004) Cofilin 1 is revealed as an inhibitor of glucocorticoid receptor by analysis of hormone-resistant cells. Mol Cell Biol 24:9371–9382

    Article  PubMed  Google Scholar 

  71. Webb BA, Zhou S, Eves R, Shen L, Jia L, Mak AS (2006) Phosphorylation of cortactin by p21-activated kinase. Arch Biochem Biophys 456:183–193

    Article  PubMed  CAS  Google Scholar 

  72. Inoue Y, Tsuda S, Nakagawa K, Hojo M, Adachi T (2011) Modeling myosin-dependent rearrangement and force generation in an actomyosin network. J Theor Biol 281:65–73

    Article  PubMed  CAS  Google Scholar 

  73. Oitzl MS, de Kloet ER (1992) Selective corticosteroid antagonists modulate specific aspects of spatial orientation learning. Behav Neurosci 106:62–71

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  75. Sandi C, Rose SP (1994) Corticosterone enhances long-term retention in one-day-old chicks trained in a weak passive avoidance learning paradigm. Brain Res 647:106–112

    Article  PubMed  CAS  Google Scholar 

  76. Sandi C, Loscertales M, Guaza C (1997) Experience-dependent facilitating effect of corticosterone on spatial memory formation in the water maze. Eur J Neurosci 9:637–642

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the National Institute of Mental Health (MH082042 to C.G. and J.L. and FMH095432A to R.S.) and the National Institute of General Medical Sciences (T32-GM0862 to R.S.). The authors would like to thank Dr. Jihua Liu, Yue Qin Yao, and Adam Katz for invaluable technical support, Elliot Handler for help with microscopy, Dr. Gary Lynch for his intellectual contributions and help with the schematic, and Dr. Tallie Z. Baram for valuable comments and discussion.

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The authors declare that they have no conflict of interest.

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  1. Department of Anatomy and Neurobiology, 3226 Gillespie Neuroscience Research Facility, University of California at Irvine, Irvine, CA, 92697-1275, USA

    Matiar Jafari, Ronald R. Seese, Alex H. Babayan & Julie C. Lauterborn

  2. Department of Anatomy and Neurobiology, 3123 Gillespie Neuroscience Research Facility, University of California at Irvine, Irvine, CA, 92697-1275, USA

    Christine M. Gall

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  1. Matiar Jafari
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Correspondence to Julie C. Lauterborn.

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Jafari, M., Seese, R.R., Babayan, A.H. et al. Glucocorticoid Receptors are Localized to Dendritic Spines and Influence Local Actin Signaling. Mol Neurobiol 46, 304–315 (2012). https://doi.org/10.1007/s12035-012-8288-3

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