Elsevier

Neuroscience

Volume 108, Issue 2, 10 December 2001, Pages 237-247
Neuroscience

Reversal of cognitive deficit of apolipoprotein E knockout mice after repeated exposure to a common environmental experience

https://doi.org/10.1016/S0306-4522(01)00412-2Get rights and content

Abstract

This study tests the hypothesis that a history of common stressful experiences further promotes the cognitive deficit of apolipoprotein E (apoE)-knockout mice, an animal model to study aspects of Alzheimer’s disease. In experiment 1, apoE-knockout and wild-type mice were repeatedly subjected to an environmental challenge (i.e. exposure to rats) and the effect was monitored on Morris water maze performance. Naive apoE-knockout mice were impaired, but surprisingly after rat stress their water maze performance improved and switched to a goal-directed search strategy. Rat stress induced in wild-type mice spatial learning deficits and an inefficient search strategy. Swim ability was not affected by rat stress and under basal conditions measures for locomotion and anxiety were similar for both genotypes. In experiments 2 and 3, we found that the rat stress paradigm attenuated the elevation of basal and stress-induced corticosterone concentrations in the apoE-knockout mice towards concentrations observed in wild-type mice. The expression of hippocampal mineralocorticoid and glucocorticoid receptor mRNA was similar in both genotypes, but in response to rat stress, the level of glucocorticoid receptor mRNA increased selectively in the CA1 pyramidal field.

In conclusion, repeated exposure to a common environmental experience did abolish and reverse the difference in cognitive performance and corticosterone concentrations of apoE-knockout and wild-type mice.

Section snippets

Animals

ApoE0/0 mice were generated as described previously by interbreeding heterozygous mutants to obtain mice homozygous for the disrupted APOE allele (van Ree et al., 1994) and backcrossed to C57Bl/6J for nine generations. Male apoE0/0 mice and wild-type controls (apoE+/+ siblings) were bred and housed under SPF conditions in the transgenic animal facilities of TNO, Leiden, the Netherlands. At 4–5 months of age, mice were transported to our department and allowed to acclimatise to their new

Water maze performance under basal conditions

Naive apoE0/0 mice are impaired in their spatial learning abilities (genotype F(1, 36)=4.22, P<0.05). After 17 training trials (day 3), apoE0/0 mice still have latencies of 40 s, while wild-type mice reached the platform within 12 s (Fig. 2A). The difference in spatial learning is also reflected in the search strategy used to locate the submerged platform. When cumulative distances to the platform are tracked with image analysis software, specific swim patterns can be distinguished, that can

Discussion

The present study demonstrates that apoE genotype differences in spatial learning as well as basal and stress-induced corticosterone secretion were eliminated after repeated exposure of mice to a common environmental experience: exposure to a rat. Although rats and mice partly share the same environment in nature, they usually avoid each other (Claassen, 1994, Linthorst et al., 2000). The corticosterone responses indeed clearly demonstrate that the encounter of mice with a rat is a stressful

Conclusion

Repeated exposure to rats abolished the differences in basal morning corticosterone, the corticosterone response to novelty and the cognitive performance between apoE0/0 and wild-type mice: apoE0/0 mice improved, while wild-types became impaired in water maze performance. This effect exerted by repeated stress appears to be mediated by corticosterone and depends on the presence of apoE.

Acknowledgements

This study was supported by the Internationale Stichting Alzheimer Onderzoek (ISAO, #679756-0270), the Netherlands Organisation for Scientific Research (NWO, #970-10-007 and #903-43-132) and EC BiotecPL960179. The technical assistance of Maaike Kempes, Leo Enthoven, Paul Lucassen and Marc Fluttert is gratefully acknowledged.

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