title: 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.
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.
authors.affiliation: UoE/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors.forename: S
authors.initials: S
authors.lastname: Caughey
authors.affiliation: UoE/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors.forename: A P
authors.initials: AP
authors.lastname: Harris
authors.affiliation: UoE/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors.forename: J R
authors.initials: JR
authors.lastname: Seckl
authors.affiliation: UoE/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors.forename: M C
authors.identifier: 0000-0001-8294-0642
authors.initials: MC
authors.lastname: Holmes
authors.affiliation: UoE/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors.forename: J L W
authors.initials: JL
authors.lastname: Yau
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000375:Aging / Q000235:genetics / Q000523:psychology*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D003345:Corticosterone / Q000097:blood; D015316:Genetic Therapy; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016548:Prosencephalon / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003345:Corticosterone
keywords: 
  BDNF
  ; ageing; corticosterone; hippocampus; watermaze