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The Journal of Neuroscience, September 26, 2007, 27(39):10487-10496; doi:10.1523/JNEUROSCI.2190-07.2007

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Behavioral/Systems/Cognitive
Enhanced Hippocampal Long-Term Potentiation and Spatial Learning in Aged 11ß-Hydroxysteroid Dehydrogenase Type 1 Knock-Out Mice

Joyce L. W. Yau,¹ Kara M. McNair,⁴ June Noble,¹ David Brownstein,³ Carina Hibberd,¹ Nik Morton,¹ John J. Mullins,² Richard G. M. Morris,⁵ Stuart Cobb,⁴ and Jonathan R. Seckl¹

¹Endocrinology Unit, ²Molecular Physiology Group, and ³Research Animal Pathology Core Facility, University of Edinburgh, Queen's Medical Research Institute, EH16 4TJ Edinburgh, United Kingdom, ⁴Neuroscience and Biomedical Systems, University of Glasgow, G12 8QQ Glasgow, United Kingdom, and ⁵Laboratory for Cognitive Neuroscience, School of Biomedical and Clinical Laboratory Sciences, University of Edinburgh, EH8 9JZ Edinburgh, United Kingdom

Correspondence should be addressed to Dr. Joyce L. W. Yau, University of Edinburgh, Endocrinology Unit, Queen's Medical Research Institute, 47 Little France Crescent, EH16 4TJ Edinburgh, UK. Email: Joyce.Yau{at}ed.ac.uk

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. 11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) amplifies local intracellular ("intracrine") glucocorticoid action; in the brain it is highly expressed in the hippocampus. We investigated whether the impact of 11ß-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" 11ß-HSD1^–/– 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 11ß-HSD1^–/– mice. Young 11ß-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 11ß-HSD1^–/– mice. These data suggest that 11ß-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.

Key words: glucocorticoids; memory; ageing; neurogenesis; LTP; hippocampus

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Received May 13, 2007; revised Aug. 8, 2007; accepted Aug. 10, 2007.

Correspondence should be addressed to Dr. Joyce L. W. Yau, University of Edinburgh, Endocrinology Unit, Queen's Medical Research Institute, 47 Little France Crescent, EH16 4TJ Edinburgh, UK. Email: Joyce.Yau{at}ed.ac.uk

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