Lack of tissue glucocorticoid reactivation in 11β-hydroxysteroid dehydrogenase type 1 knockout mice ameliorates age-related learning impairments

Joyce L.W. Yau, June Noble, Christopher J. Kenyon, Carina Hibberd, Yuri Kotelevtsev, John J. Mullins, Jonathan R. Seckl

Research output: Contribution to journalArticlepeer-review

169 Citations (Scopus)

Abstract

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) intracellularly regenerates active corticosterone from circulating inert 11-dehydrocorticosterone (11-DHC) in specific tissues. The hippocampus is a brain structure particularly vulnerable to glucocorticoid neurotoxicity with aging. In intact hippocampal cells in culture, 11β-HSD-1 acts as a functional 11β-reductase reactivating inert 11-DHC to corticosterone, thereby potentiating kainate neurotoxicity. We examined the functional significance of 11β-HSD-1 in the central nervous system by using knockout mice. Aged wild-type mice developed elevated plasma corticosterone levels that correlated with learning deficits in the watermaze. In contrast, despite elevated plasma corticosterone levels throughout life, this glucocorticoid-associated learning deficit was ameliorated in aged 11β-HSD-1 knockout mice, implicating lower intraneuronal corticosterone levels through lack of 11-DHC reactivation. Indeed, aged knockout mice showed significantly lower hippocampal tissue corticosterone levels than wild-type controls. These findings demonstrate that tissue corticosterone levels do not merely reflect plasma levels and appear to play a more important role in hippocampal functions than circulating blood levels. The data emphasize the crucial importance of local enzymes in determining intracellular glucocorticoid activity. Selective 11β-HSD-1 inhibitors may protect against hippocampal function decline with age.

Original languageEnglish
Pages (from-to)4716-4721
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number8
DOIs
Publication statusPublished - 10 Apr 2001
Externally publishedYes

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