Cyclic changes in estradiol regulate synaptic plasticity through the MAP kinase pathway

Hippocampal synaptic structure and function exhibit marked variations during the estrus cycle of female rats. Estradiol activates the mitogen-activated protein (MAP) kinase pathway in numerous cell types, and MAP kinase has been shown to play a critical role in the mechanisms underlying synaptic plasticity. Here, we report that endogenous estrogen produces a tonic phosphorylation/activation of extracellular signal-regulated kinase 2 (ERK2)/MAP kinase throughout the female rat brain and an increase in tyrosine phosphorylation of NR2 subunits of N-methyl-D-aspartate (NMDA) receptors. Moreover, cyclic changes in estrogen levels during the estrus cycle of female rats are associated with corresponding changes in the levels of activation of ERK2, the state of tyrosine phosphorylation of NR2 subunits of NMDA receptors, and the magnitude of long-term potentiation in hippocampus. Thus, cyclic changes in female sexual hormones result in marked variations in the state of activation of a major cellular signaling pathway critical for learning and memory and in a cellular model of learning and memory.