title: Glucocorticoid receptor activation impairs hippocampal plasticity by suppressing BDNF expression in obese mice.
abstract: Diabetes and obesity are associated with perturbation of adrenal steroid hormones and impairment of hippocampal plasticity, but the question of whether these conditions recruit glucocorticoid-mediated molecular cascades that are comparable to other stressors has yet to be fully addressed. We have used a genetic mouse model of obesity and diabetes with chronically elevated glucocorticoids to determine the mechanism for glucocorticoid-induced deficits in hippocampal synaptic function. Pharmacological inhibition of adrenal steroidogenesis attenuates structural and functional impairments by regulating plasticity among dendritic spines in the hippocampus of leptin receptor deficient (db/db) mice. Synaptic deficits evoked by exposure to elevated corticosterone levels in db/db mice are attributable to glucocorticoid receptor-mediated transrepression of AP-1 actions at BDNF promoters I and IV. db/db mice exhibit corticosterone-mediated reductions in brain-derived neurotrophic factor (BDNF), and a change in the ratio of TrkB to P75NTR that silences the functional response to BDNF stimulation. Lentiviral suppression of glucocorticoid receptor expression rescues behavioral and synaptic function in db/db mice, and also reinstates BDNF expression, underscoring the relevance of molecular mechanisms previously demonstrated after psychological stress to the functional alterations observed in obesity and diabetes.
authors.affiliation: Department of Physiology, Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Marlena
authors.initials: M
authors.lastname: Wosiski-Kuhn
authors.affiliation: Department of Physiology, Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Erion
authors.affiliation: G.V. (Sonny) Montgomery Veteran's Affairs Medical Center, 1500 Woodrow Wilson Drive, Jackson, Jackson, MS 39216, USA.
authors.forename: Elise P
authors.initials: EP
authors.lastname: Gomez-Sanchez
authors.affiliation: G.V. (Sonny) Montgomery Veteran's Affairs Medical Center, 1500 Woodrow Wilson Drive, Jackson, Jackson, MS 39216, USA.
authors.forename: Celso E
authors.initials: CE
authors.lastname: Gomez-Sanchez
authors.affiliation: Department of Physiology, Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA. Electronic address: astranahan@gru.edu.
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Stranahan
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008820:Mice, Obese; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D011965:Receptors, Glucocorticoid; D013252:Steroid 11-beta-Hydroxylase; D008797:Metyrapone
keywords: Corticosterone; Dendritic spine; Dentate gyrus; Hippocampus; Long-term potentiation; Synapse; Synaptic plasticity