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Forebrain-specific transgene rescue of 11β-HSD1 associates with impaired spatial memory and reduced hippocampal BDNF mRNA levels in aged 11β-HSD1 deficient mice

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Original languageEnglish
JournalJournal of Neuroendocrinology
Early online date17 Nov 2016
Publication statusE-pub ahead of print - 17 Nov 2016


Mice lacking the intracellular glucocorticoid-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) are protected from age-related spatial memory deficits. 11β-HSD1 is expressed predominantly in brain, liver and adipose tissue. Reduced glucocorticoid levels in brain in the absence of 11β-HSD1 may underlie the improved memory in aged 11β-HSD1 deficient mice. However, the improved glucose tolerance, insulin sensitization and cardio-protective lipid profile associated with reduced peripheral glucocorticoid regeneration may potentially contribute to the cognitive phenotype of aged 11β-HSD1 deficient mice. In this study, transgenic mice with forebrain-specific overexpression of 11β-HSD1 (Tg) were inter-crossed with global 11β-HSD1 knockout mice (HSD1KO) to examine the influence of forebrain and peripheral 11β-HSD1 activity on spatial memory in aged mice. Transgene-mediated delivery of 11β-HSD1 to the hippocampus and cortex of aged HSD1KO mice reversed the improved spatial memory retention in the Y-maze but not spatial learning in the watermaze. Brain-derived neurotrophic factor (BDNF) mRNA levels in the hippocampus of aged HSD1KO mice were increased compared to aged wild type mice. Rescue of forebrain 11β-HSD1 reduced BDNF mRNA in aged HSD1KO mice to levels comparable to aged wild type mice. These findings indicate that 11β-HSD1 regenerated glucocorticoids in forebrain and decreased levels of BDNF mRNA in the hippocampus plays a role in spatial memory deficits in aged wild type mice but 11β-HSD1 activity in peripheral tissues may also contribute to spatial learning impairments in aged mice. This article is protected by copyright. All rights reserved.

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