Glucocorticoid receptors are localized to dendritic spines and influence local actin signaling.
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.
Department of Anatomy and Neurobiology, 3226 Gillespie Neuroscience Research Facility, University of California at Irvine, Irvine, CA 92697-1275, USA.
Matiar
M
Jafari
Ronald R
RR
Seese
Alex H
AH
Babayan
Christine M
CM
Gall
Julie C
JC
Lauterborn
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000818:Animals; D049229:Dendritic Spines / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000201:enzymology; D054462:p21-Activated Kinases / Q000378:metabolism
D051339:Actin Depolymerizing Factors; D000199:Actins; D003907:Dexamethasone; D048049:Extracellular Signal-Regulated MAP Kinases; D051860:Fragile X Messenger Ribonucleoprotein 1; D005938:Glucocorticoids; D049452:Green Fluorescent Proteins; D011965:Receptors, Glucocorticoid; D018094:Receptors, Metabotropic Glutamate; D054462:p21-Activated Kinases