Glucocorticoid Receptors are Localized to Dendritic Spines and Influence Local Actin Signaling
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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.
KeywordsDexamethasone Extracellular signal-regulated kinase Fragile X Mental Retardation Protein Cofilin Rho GTPase Glucocorticoid receptor
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.
Conflict of Interest
The authors declare that they have no conflict of interest.
- 5.Evanson NK, Herman J, P., Sakai RR, Krause EG (2010) Nongenomic actions of adrenal steroids in the central nervous system. J Neuroendocrinol. 846–861Google 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 335:1002–1007PubMedCrossRefGoogle 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 78:23–33Google 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) 100:85–90Google 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 40:239–257PubMedCrossRefGoogle 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 DiegoGoogle Scholar