Point mutation in the mouse glucocorticoid receptor preventing DNA bindingimpairs spatial memory

Activation of central glucocorticoid receptors caused by the stress that is associated with a learning task facilitates storage of the acquired inform ation. The molecular mechanism underlying this phenomenon is entirely unkno wn. Glucocorticoid receptors can influence transcription both through DNA b inding-dependent and -independent mechanisms. To assess the importance of t hese 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 c an take place. These mice showed a selective impairment of spatial memory i n 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 un der basal resting conditions and in response to swimming, which could have influenced memory processes of the mice. However, mimicking the task-relate d increase in corticosterone by supplementary injection of corticosterone ( 250 mug/kg, i.p.) in adrenalectomized mice, resulting in equal plasma corti costerone concentrations in both genotypes, improved spatial memory of cont rol mice but had no effect on mutant mice. These findings suggest that task -related facilitating effects of corticosterone on spatial memory indeed de pend on DNA binding of the glucocorticoid receptor rather than on protein-p rotein interactions of the receptor with other transcription factors. Altho ugh it cannot be excluded that both processes are involved in a coordinated way, interrupting the DNA-binding capacity of the receptor is sufficient t o induce impairment.