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

11 beta -hydroxysteroid dehydrogenase type 1 (11 beta -HSD-1) intracellular ly regenerates active corticosterone from circulating inert 11-dehydrocorti costerone (11-DHC) in specific tissues. The hippocampus is a brain structur e particularly vulnerable to glucocorticoid neurotoxicity with aging. In in tact hippocampal cells in culture, 11 beta -HSD-1 acts as a functional 11 b eta -reductase reactivating inert 11-DHC to corticosterone, thereby potenti ating kainate neurotoxicity. We examined the functional significance of 11 beta -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 plas ma corticosterone levels throughout life, this glucocorticoid-associated le arning deficit was ameliorated in aged 11 beta -HSD-1 knockout mice, implic ating lower intraneuronal corticosterone levels through lack of 11-DHC reac tivation. Indeed, aged knockout mice showed significantly lower hippocampal tissue corticosterone levels than wild-type controls. These findings demon strate that tissue corticosterone levels do not merely reflect plasma level s and appear to play a more important role in hippocampal functions than ci rculating blood levels. The data emphasize the crucial importance of local enzymes in determining intracellular glucocorticoid activity. Selective 11 beta -HSD-1 inhibitors may protect against hippocampal function decline wit h age.