Prevention of age-related dysregulation of calcium dynamics by estrogen in neurons

To determine the impact of aging and 17β-estradiol on neuronal Ca ²⁺ homeostasis, intracellular Fura-2 Ca²⁺-imaging was conducted during 20-pulses of glutamate in hippocampal neurons cultured from embryonic (E18), middle-age (10 months) and old (24 months) rat brain. Marked age-related differences in intracellular Ca²⁺ ([Ca²⁺]i) homeostasis and striking regulation by 17β-estradiol were seen. Embryonic neurons exhibited the greatest capacity to regulate Ca²⁺ homeostasis followed by middle-age neurons. In old neurons, the first peak [Ca ²⁺]i was substantially greater than at other ages and the return to baseline Ca²⁺ rapidly dysregulated with an inability to restore [Ca²⁺]i following the first glutamate pulse which persisted throughout the 20 pulses. 17β-Estradiol pretreatment of old neurons profoundly attenuated the peak [Ca²⁺]i rise and delayed the age-associated dysregulation of baseline [Ca²⁺]i, normalizing responses to those of middle-age neurons treated with estradiol. The efficacy of 17β-estradiol extended below 10 pg/ml with full protection against toxicity from glutamate and Aβ (1-40). These results demonstrate age-associated dysregulation of [Ca²⁺]i homeostasis which was largely prevented by 17β-estradiol with implications for estrogen/hormone therapy.