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

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 dim͞dim ) while proteinprotein 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 light͞dark 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 g͞kg, 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.

Behavioral deficits associated with fetal alcohol exposure are reversed by prenatal thyroid hormone treatment: a role for maternal thyroid hormone deficiency in FAE

“…[79][80][81] Decreased expression or binding capacity of the hippocampal GR is known to result in impaired spatial learning. [82][83][84] However, we did not find an effect of FAE on hippocampal GR expression, which is in agreement with a previous report. 85 Fetal overexposure to endogenous glucocorticoids, such that occurs after reducing the activity of the 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2), the 'barrier' enzyme to maternal steroids that rapidly inactivates glucocorticoids in placenta and many fetal tissues, affects neuroendocrine and behavioral responses of the adult offspring.…”

Stress at Learning Facilitates Memory Formation by Regulating AMPA Receptor Trafficking Through a Glucocorticoid Action

“…By contrast, metyrapone had no effect on synaptic GluA1 expression (data not shown). To investigate the involvement of GR receptorsFwhich mediate corticosterone actions and were shown to be essential for consolidation of long-term spatial memory (Oitzl et al, 2001)Fwe injected the GR antagonist RU38486 before training and found that it inhibited the increase in GluA2 observed in 221C-trained mice (Figure 3e; RU vs Ctrl po0.05). Corticosterone injections (10 mg/kg; i.p.)…”

Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways

“…These mice have normal hypothalamic CRH expression, increased pituitary proopiomelanocortin (POMC) expression, normal plasma ACTH levels, and increased plasma corticosterone levels. They also exhibit impaired spatial memory but normal anxiety-like behavior [38]. Mice that overexpress the glucocorticoid receptor (YGR mice) have a marked decrease in hypothalamic CRH and pituitary POMC expression, increased plasma ACTH levels, and decreased plasma corticosterone levels [39].…”