ABSTRACT
Our investigations into estrogen regulation of mitochondrial function grew out of a paradox. Our earlier results demonstrated that pretreatment of neurons with estrogen replacement therapy could either potentiate or attenuate glutamateinduced rise in intracellular Ca2+ ([Ca2+]i), depending on the glutamate concentration
1,2. Weknew from our results and those of other laboratories that estrogen induction of memory mechanisms required potentiation of the glutamate N-methyl-D-aspartate (NMDA) receptor3-5. Initially, one would predict and be concerned that potentiation of the glutamate NMDA receptor function would lead to excitotoxicity. However, a large body of evidence indicated that estrogen was quite effective in protecting against glutamate-induced excitotoxicity3,6-8. Wesoughtto understand the mechanism(s) whereby estrogen could both potentiate glutamate NMDA receptor function and yet protect against glutamateinduced excitotoxicity. Pursuing this question, we found that estrogen replacement therapy attenuated glutamateinduced rise in [Ca2+]i
1,2. What puzzled us about this result was that our experimental paradigm used a prevention model of estrogen exposure, that is, neurons were pretreated with estrogen prior to exposure to glutamate but neurons responded diametrically differently, either potentiating or attenuating glutamate-induced rise in [Ca2+]i, depending on the subsequent exposure to either non-toxic or excitotoxic glutamate concentrations. These data indicated that estrogen exposure proactively activated a mechanism that would protect against excesses in [Ca2+]i.. We therefore began to explore what mechanisms would account for the estrogen’s proactive protection.
