Glucocorticoid receptor activation impairs hippocampal plasticity by suppressing BDNF expression in obese mice

• Published in: Psychoneuroendocrinology 2014-04, Vol.42, p.165-177
• Main Authors: Wosiski-Kuhn, Marlena, Erion, Joanna R, Gomez-Sanchez, Elise P, Gomez-Sanchez, Celso E, Stranahan, Alexis M
• Format: Article
• Language: English
• Subjects: Animals; Behavioral psychophysiology; Biological and medical sciences; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - metabolism; Corticosterone; Dendritic spine; Dentate gyrus; Endocrinology & Metabolism; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Hormones and behavior; Long-term potentiation; Medical sciences; Metabolic diseases; Metyrapone - pharmacology; Mice; Mice, Obese; Neuronal Plasticity - drug effects; Neuronal Plasticity - physiology; Obesity; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Receptors, Glucocorticoid - metabolism; Steroid 11-beta-Hydroxylase - antagonists & inhibitors; Synapse; Synaptic plasticity
• ISSN: 0306-4530; 1873-3360
• DOI: 10.1016/j.psyneuen.2014.01.020

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.