Forebrain-Specific Transgene Rescue of 11β-HSD1 Associates with Impaired Spatial Memory and Reduced Hippocampal Brain-Derived Neurotrophic Factor mRNA Levels in Aged 11β-HSD1 Deficient Mice.

S Caughey,A P Harris,J L W Yau,M C Holmes,J R Seckl

doi:10.1111/jne.12447

Abstract

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 the brain, liver and adipose tissue. Reduced glucocorticoid levels in the brain in the absence of 11β‐HSD1 may underlie the improved memory in aged 11β‐HSD1 deficient mice. However, the improved glucose tolerance, insulin sensitisation and cardioprotective lipid profile associated with reduced peripheral glucocorticoid regeneration may potentially contribute to the cognitive phenotype of aged 11β‐HSD1 deficient mice. In the present study, transgenic mice with forebrain‐specific overexpression of 11β‐HSD1 (Tg) were intercrossed 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 the forebrain and decreased levels of BDNF mRNA in the hippocampus play a role in spatial memory deficits in aged wild‐type mice, although 11β‐HSD1 activity in peripheral tissues may also contribute to spatial learning impairments in aged mice.

Highlights

Elevated circulating glucocorticoids (GC; cortisol in humans and corticosterone in rodents) as a consequence of impaired hypothalamic-pituitary-adrenal (HPA) negative feedback regulation often accompanies ageing and cognitive decline [1,2,3]
Rescue of forebrain 11β-HSD1 reduced Brain-derived neurotrophic factor (BDNF) mRNA in aged HSD1 knockout mice (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 contribute to spatial learning impairments in aged mice
When HSD1KO mice were bred with transgenic mice with forebrain-specific overexpression of 11β-HSD1 (Tg mice) to generate Tg+HSD1KO mice, 11β-HSD1 activity was recovered in hippocampus and cortex to levels similar to WT controls but remained absent in liver (Fig. 1)

Summary

Introduction

Elevated circulating glucocorticoids (GC; cortisol in humans and corticosterone in rodents) as a consequence of impaired hypothalamic-pituitary-adrenal (HPA) negative feedback regulation often accompanies ageing and cognitive decline [1,2,3]. Animal studies have shown chronic stress or high GC levels cause hippocampal dendritic atrophy, impaired synaptic plasticity, decreased neurogenesis and impaired memory [6, 7]. Maintenance of low corticosterone (CORT) levels throughout life in rats prevents age-associated hippocampal morphology changes and impairs cognition supporting high CORT levels as a cause rather than a consequence of hippocampal damage [8]. GC levels can be modulated by the action of 11βhydroxysteroid dehydrogenases which interconvert active and inactive GCs. 11β-HSD1 is highly expressed in liver, adipose tissue and brain where it acts predominantly as a 11βreductase in vivo to regenerate active GCs (cortisol, corticosterone) within cells from inert 11-keto forms (cortisone, 11-dehydrocorticosterone) effectively amplifying local GC levels [10]. 11β-HSD1 is the sole isozyme expressed in regions important for cognition such as hippocampus and cortex [10]

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Results

Conclusion