11β-Hydroxysteroid Dehydrogenase Type 1 Expression Is Increased in the Aged Mouse Hippocampus and Parietal Cortex and Causes Memory Impairments

Megan C. Holmes, Roderick N. Carter, June Noble, Shruti Chitnis, Amy Dutia, Janice M. Paterson, John J. Mullins, Jonathan R. Seckl, Joyce L. W. Yau

Research output: Contribution to journalArticlepeer-review

Abstract

Increased neuronal glucocorticoid exposure may underlie interindividual variation in cognitive function with aging in rodents and humans. 11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyzes the regeneration of active glucocorticoids within cells (in brain and other tissues), thus amplifying steroid action. We examined whether 11 beta-HSD1 plays a role in the pathogenesis of cognitive deficits associated with aging in male C57BL/6J mice. We show that 11 beta-HSD1 levels increase with age in CA3 hippocampus and parietal cortex, correlating with impaired cognitive performance in the water maze. In contrast, neither circulating corticosterone levels nor tissue corticosteroid receptor expression correlates with cognition. 11 beta-HSD1 elevation appears causal, since aging (18 months) male transgenic mice with forebrain-specific 11 beta-HSD1 overexpression (similar to 50% in hippocampus) exhibit premature age-associated cognitive decline in the absence of altered circulating glucocorticoid levels or other behavioral (affective) deficits. Thus, excess 11 beta-HSD1 in forebrain is a cause of as well as a therapeutic target in memory impairments with aging.

Original languageEnglish
Pages (from-to)6916-6920
Number of pages5
JournalThe Journal of Neuroscience
Volume30
Issue number20
DOIs
Publication statusPublished - 19 May 2010

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