Point mutation in the mouse glucocorticoid receptor preventing DNA binding impairs spatial memory.
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.
Oitzl
M S
MS
Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, P.O. Box 9503, Leiden University Medical Center, 2300 RA Leiden, The Netherlands. m.oitzl@lacdr.leidenuniv.nl
Reichardt
H M
HM
Joëls
M
M
de Kloet
E R
ER
D000818:Animals; D003345:Corticosterone / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D008297:Male; D018782:Maze Learning; D008569:Memory Disorders / Q000209:etiology*; D051379:Mice; D017354:Point Mutation; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000502:physiology*
D011965:Receptors, Glucocorticoid; D004247:DNA; D003345:Corticosterone