Membrane bound ERs may be involved in a very rapid nongenomic action of estrogens in the brain [55]. Singh et al. reported that estrogen induced phosphorylation of ERKs was not lost in cortical neurones from ERα knockout mice, therefore suggesting ERα may not mediate the rapid phospho-ERK enhancing effects of estrogen [56]. Similarly, Sheldahl et al. in 2008 showed that estrogen induces rapid translocation of ERβ but not ERα in the neuronal plasma membrane. In contrast, Abraham et al. reported that rapid estrogen dependent induction of ERKs phosphorylation in the medial preoptic nucleus was lost in both ERα and ERβ knockout mice, suggesting that both ERα and ERβ may mediate the ERK regulatory effects of estrogen [57]. Finally, estrogen can also rapidly induce c-fos protein in the brain, an effect which has been shown to be lost in double ERα/ERβ knockout mice in ventral medial nucleus, preoptic area, granule accessory layer of preoptic bulb and pyramidal layer of CA3 hippocampus [58] (Fig. 2).