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. 2001 Oct 23;98(22):12790-5.
doi: 10.1073/pnas.231313998. Epub 2001 Oct 16.

Point mutation in the mouse glucocorticoid receptor preventing DNA binding impairs spatial memory

M S Oitzl  1 , H M Reichardt, M Joëls, E R de Kloet
Affiliations

Point mutation in the mouse glucocorticoid receptor preventing DNA binding impairs spatial memory

M S Oitzl et al. Proc Natl Acad Sci U S A. .

Abstract

Activation of central glucocorticoid receptors caused by the stress that is associated with a learning task facilitates storage of the acquired information. The molecular mechanism underlying this phenomenon is entirely unknown. Glucocorticoid receptors can influence transcription both through DNA binding-dependent and -independent mechanisms. To assess the importance of these two modes of action for spatial memory, we here used male mutant mice in which homodimerization and DNA binding of the glucocorticoid receptor is largely prevented (GR(dim/dim)) while protein-protein interactions still can take place. These mice showed a selective impairment of spatial memory in the water maze. Locomotion and anxiety-related parameters measured in an open field and a light/dark preference task were comparable for mutant and control mice. Mutant mice released more corticosterone than control mice under basal resting conditions and in response to swimming, which could have influenced memory processes of the mice. However, mimicking the task-related increase in corticosterone by supplementary injection of corticosterone (250 microg/kg, i.p.) in adrenalectomized mice, resulting in equal plasma corticosterone concentrations in both genotypes, improved spatial memory of control mice but had no effect on mutant mice. These findings suggest that task-related facilitating effects of corticosterone on spatial memory indeed depend on DNA binding of the glucocorticoid receptor rather than on protein-protein interactions of the receptor with other transcription factors. Although it cannot be excluded that both processes are involved in a coordinated way, interrupting the DNA-binding capacity of the receptor is sufficient to induce impairment.

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Figures

Figure 1
Figure 1
Water maze performance of GRdim/dim and control mice. Distance in cm (A) and latency in sec (B) to reach the submerged platform were enhanced in GRdim/dim relative to control mice from day 2 onward. Swim velocity in cm/sec (C) was lower in GRdim/dim mice. Data are expressed as mean ± SEM. *, P < 0.05 between groups during spatial training trials.
Figure 2
Figure 2
Cumulative distance in cm to trained platform and three arbitrary locations during free swim trials in the absence of the platform in GRdim/dim (A) and control mice (B). Cumulative distance is the measure of the position of the swimming mouse with respect to platform locations, calculated five times per second during the first 30 sec of the free swim trials. Spatial training markedly reduced the cumulative distance in both groups, with control mice expressing the shortest distance to the trained platform location. *, P < 0.05 trained platform location versus arbitrary platform locations in the other quadrants of the pool. (Inset) Training location of submerged platform (black) and other possible platform locations. The shading of the platform locations in the Inset corresponds with the bars in A and B.
Figure 3
Figure 3
Corticosterone response (ng/ml) to 1 min of swimming. Basal values were estimated on the day before swimming. The time points 15, 30, 90, and 180 min give corticosterone concentrations in plasma measured in the home cage after swimming. *, P < 0.05 GRdim/dim versus control group.
Figure 4
Figure 4
Water maze performance of adrenalectomized (ADX) control (A) and GRdim/dim (B) mice. Arrows indicate that the mice were injected with corticosterone (250 μg/kg i.p.; filled symbols) or vehicle (0.2 ml of saline/25 g of bodyweight; open symbols) before the daily training trials. Corticosterone improved the performance of adrenalectomized control but not of GRdim/dim mice. The data represent mean distance to platform in cm (± SEM)/day. *, P < 0.05 between groups.
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References

    1. McEwen B S, de Kloet E R, Rostene W. Physiol Rev. 1986;66:1121–1188. - PubMed
    1. de Kloet E R. Front Neuroendocrinol. 1991;12:95–164.
    1. Oitzl M S, Fluttert M, de Kloet E R. Eur J Neurosci. 1994;6:1072–1079. - PubMed
    1. Sandi C, Rose S P R. Brain Res. 1994;647:106–112. - PubMed
    1. Sandi C, Loscertales M, Guaza C. Eur J Neurosci. 1997;9:637–642. - PubMed

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