Hippocampal glucocorticoid receptor activation enhances voltage-dependent Ca²⁺ conductances: Relevance to brain aging

Glucocorticoids (GCs) activate several biochemical/molecular processes in the hippocampus through two receptor types. In addition, GCs influence cognitive behaviors and hippocampal neural activity and can also increase the rate of aging-dependent cell loss in the hippocampus. However, the ionic mechanisms through which GCs modulate hippocampal neuronal function are not well understood. We report here direct evidence that activation of cytosolic steroid receptors, specifically of the type II GC receptor, can enhance voltage-dependent Ca²⁺ conductances in brain neurons. Ca2+ current was assessed by current-clamp measures of Ca²⁺ action potentials and by sharp electrode voltage-clamp analyses of voltage-sensitive currents in cesium-, tetrodotoxin-, and tetraethylanunonium-treated CA1 neurons in hippocampal slices. Both Ca²⁺ action potentials and voltage-activated Ca²⁺ currents (N- and L-like) were increased by 2-hr exposure to the synthetic GC receptor agonist, RU 28362. This effect of RU 28362 was blocked by coincubation with cycloheximide, indicating that the GC receptor-Ca²⁺ channel interaction depends on de novo protein synthesis. Dysregulated calcium homeostasis is also viewed as a candidate mechanism in brain aging. Thus, present results are consistent with the hypothesis that excessive GC-receptor activation and resultant increased Ca²⁺ influx may be two sequential phases of a brain-aging process that results initially in impairment of function and eventually in neuronal loss.