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. 2007 Sep 26;27(39):10487-96.
doi: 10.1523/JNEUROSCI.2190-07.2007.

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

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

Joyce L W Yau et al. J Neurosci. .
Free PMC article

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

Figures

Figure 1.
Figure 1.
Aged 11β-HSD1−/− mice show better spatial learning than age-matched C57BL/6J controls. A, B, Performance in the spatial water-maze task as illustrated by mean escape latencies (block of 4 trials; A), average swim speeds for each day of training (B), trial 1 latencies for each day of training (C), and trial 1 path lengths to platform for each day of training (D). Each point represents the mean ± SEM. *p < 0.05 compared with all other groups. Two aged mice from each genotype were excluded after failing the criteria in the visible task (see Materials and Methods).
Figure 2.
Figure 2.
A, Similar performances of C57BL/6J controls (n = 10–14) and 11β-HSD1−/− mice (n = 10–12) in the Y maze 1 min after the first encounter with the maze. B, Impaired hippocampal learning and memory in old C57BL/6J (12 and 24 months), but not 11β-HSD1−/− mice in the Y maze 2 h after initial encounter with one arm closed. *p < 0.05 compared with C57BL/6J (3 months) controls, §p < 0.01 compared with age-matched C57BL/6J controls.
Figure 3.
Figure 3.
A, Plasma CORT levels from morning tail venesection blood samples from young (5 months; n = 5 per group) and aged (26 months; n = 10 per group) C57BL/6J (C57) controls and 11β-HSD1−/− (KO) mice. *p < 0.001 compared with young controls. B, Plasma CORT levels after a 10 min restraint stress in aged (26 months) 11β-HSD1−/− and C57BL/6J mice (n = 4 per group). *p < 0.001 compared with young mice of corresponding genotype.
Figure 4.
Figure 4.
A, Glucose tolerance in aged (26 months) C57BL/6J control (n = 4) and 11β-HSD1−/− mice (n = 5). Plasma glucose levels were measured from mice fasted overnight and given a glucose load (2 mg/g d-glucose, i.p.). B, Fasting (16 h) blood insulin levels in young (5 months) and aged (26 months) 11β-HSD1−/− (KO) and C57BL/6J (C57) control mice. C, The ratio of fasting insulin to glucose used as an index of insulin resistance. Results represent the means ± SEM. *p < 0.05 compared with the indicated group. n = 7 young C57, 8 young KO, 8 aged C57, and 4 aged KO mice.
Figure 5.
Figure 5.
The effect of high-frequency stimulation (100 Hz; 1 s) in the CA1 region on positive EPSP slope in aged (26 months) mouse hippocampal slices. A, B, The stable baseline EPSP in the control unstimulated pathway in both C57BL/6J control (A) and 11β-HSD1−/− mice (B) indicates that the potentiation was input specific. C, LTP was significantly enhanced (p < 0.05) in 11β-HSD1−/− mice (n = 6; 15 slices) compared with C57BL/6J mice (n = 5; 10 slices).
Figure 6.
Figure 6.
Young 11β-HSD1−/− mice show increased hippocampal neurogenesis. Young (5 months) 11β-HSD1−/− mice (n = 7) show increased BrdU-immunoreactive (BrdU-IR) cells in the SGZ, but not the hilus area of the dentate gyrus compared with young (5 months) C57BL/6J mice (n = 5). The inset shows 40× microscopic images of the BrdU-IR cells in the SGZ of young C57BL/6J and 11β-HSD1−/− mice. Both aged (22–25 months) 11β-HSD1−/− (n = 7) and control C57BL/6J mice (n = 7) show decreased BrdU-IR cells [with very few BrdU-IR cells detected per section in the SGZ (data not shown)] compared with young controls. Values are means ± SEM. *p < 0.05 compared with young C57BL/6J controls; §p < 0.001 compared with young mice of the corresponding genotype.

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