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

Marlena Wosiski-Kuhn, Joanna Ruth Appel, Elise P. Gomez-Sanchez, Celso E. Gomez-Sanchez, Alexis Michelle Stranahan

Research output: Contribution to journalArticle

45 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)165-177
Number of pages13
JournalPsychoneuroendocrinology
Volume42
DOIs
StatePublished - Jan 1 2014

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Keywords

  • Corticosterone
  • Dendritic spine
  • Dentate gyrus
  • Hippocampus
  • Long-term potentiation
  • Synapse
  • Synaptic plasticity

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology
  • Endocrine and Autonomic Systems
  • Psychiatry and Mental health
  • Biological Psychiatry

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