Enhanced Hippocampal Long-Term Potentiation and Spatial Learning in Aged 11β-Hydroxysteroid Dehydrogenase Type 1 Knock-Out Mice

Abstract

Glucocorticoids are pivotal in the maintenance of memory and cognitive functions as well as other essential physiological processes including energy metabolism, stress responses, and cell proliferation. Normal aging in both rodents and humans is often characterized by elevated glucocorticoid levels that correlate with hippocampus-dependent memory impairments. 11␤-Hydroxysteroid dehydrogenase type 1 (11␤-HSD1) amplifies local intracellular ("intracrine") glucocorticoid action; in the brain it is highly expressed in the hippocampus. We investigated whether the impact of 11␤-HSD1 deficiency in knock-out mice (congenic on C57BL/6J strain) on cognitive function with aging reflects direct CNS or indirect effects of altered peripheral insulin-glucose metabolism. Spatial learning and memory was enhanced in 12 month "middle-aged" and 24 month "aged" 11␤-HSD1Ϫ/Ϫ mice compared with age-matched congenic controls. These effects were not caused by alterations in other cognitive (working memory in a spontaneous alternation task) or affective domains (anxiety-related behaviors), to changes in plasma corticosterone or glucose levels, or to altered age-related pathologies in 11␤-HSD1 ؊/؊ mice. Young 11␤-HSD1 ؊/؊ mice showed significantly increased newborn cell proliferation in the dentate gyrus, but this was not maintained into aging. Long-term potentiation was significantly enhanced in subfield CA1 of hippocampal slices from aged 11␤-HSD1 ؊/؊ mice. These data suggest that 11␤-HSD1 deficiency enhances synaptic potentiation in the aged hippocampus and this may underlie the better maintenance of learning and memory with aging, which occurs in the absence of increased neurogenesis.

11β-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects

“…In these tissues, increased local GC activation is postulated to contribute to the increased risk of fracture and osteoporosis and impaired cognitive function associated with aging. Improved cognition and increased long-term potentiation have been reported in aged 11β-HSD1 KO mice relative to age-matched controls (32), with improved memory consolidation, recall, and social recognition also reported following treatment with specific 11β-HSD1 inhibitors (33,34).…”

Acute Inhibition of 11β-Hydroxysteroid Dehydrogenase Type-1 Improves Memory in Rodent Models of Cognition

“…Aged C57BL/6 mice show watermaze deficits that correlate with increased HSD1 expression in the hippocampus and forebrain; overexpression of HSD1 similarly impaired performance (Holmes et al, 2010). Conversely, aged HSD1 knock-out mice have improved cognition and increased long-term potentiation relative to age-matched controls, suggesting a neuroprotective effect of HSD1 inhibition (Yau et al, 2001(Yau et al, , 2007. The nonselective 11␤-hydroxysteroid dehydrogenase inhibitor carbenoxolone improved verbal memory in elderly men and type II diabetics (Sandeep et al, 2004).…”

Contributions of impaired hippocampal plasticity and neurodegeneration to age-related deficits in hormonal pulsatility

“…More recently, the enzyme 11-β-hydroxysteroid dehydrogenase-1 (11βHSD-1), which increases local corticosterone availability by generating corticosterone from inactive cortisone, has been shown to play a role in mediating the effects of ageing-induced elevations in glucocorticoids. Transgenic mice lacking 11βHSD-1 show attenuation of age-related cognitive impairment and restoration of hippocampal synaptic plasticity (Yau et al, 2007). These results indicate that reducing local corticosterone actions in the brain by modulating 11βHSD1 can attenuate functional deficits.…”