Calcineurin as a potential contributor in estradiol regulation of hippocampal synaptic function

Abstract

Estradiol influences Ca 2+ regulation and Ca 2+-dependent synaptic plasticity, suggesting estrogenic effects on Ca 2+-dependent enzymes that regulate synaptic plasticity may mediate hormonal influences on cognition. In ovariectomized female rats, injections of estradiol benzoate (EB, 10 μg) reduced hippocampal cytosolic activity of serine/threonine protein phosphatases, calcineurin and protein phosphatase 1 (PP1). The decreased activity was rapid and recovered substantially over a 24-h period. Decreased calcineurin activity was associated with a decreased level of calcineurin in the cytosol. In contrast, expression of PP1 was not altered suggesting that the level of calcineurin activity regulated PP1 activity. EB application to hippocampal slices rapidly decreased cytosolic phosphatase activity, which was not blocked by the estrogen receptor antagonist, ICI 182780. Decreased phosphatase activity was associated with an increase in CA3–CA1 synaptic transmission. In addition, EB application shifted synaptic plasticity, blocking the induction of long-term depression and facilitating the establishment of long-term potentiation. The reduction in calcineurin activity and shift in synaptic plasticity were mimicked to a lesser extent by 17-α-estradiol. From these results we suggest that EB can act to rapidly influence Ca 2+ signaling pathways including the activity of Ca 2+-regulated phosphatases involved in synaptic plasticity.