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

Marlena Wosiski-Kuhn, Joanna R. Erion, Elise P. Gomez-Sanchez, Celso E. Gomez-Sanchez, Alexis M. Stranahan

Research output: Contribution to journalArticlepeer-review

46 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 - Apr 2014

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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