beta-estradiol influences differentiation of hippocampal neurons in vitro through an estrogen receptor-mediated...

We utilized morphometric analysis of 3 day cultures of hippocampal neurons to determine the effects of both estradiol and the synthetic estrogen receptor modulator raloxifene on several parameters of neuronal growth and differentiation. These measurements included survival, neurite production, dendrite number, and axon and dendrite length and branching. 17 beta-Estradiol (10 nM) selectively stimulated dendrite branching; this effect was neither mimicked by alpha-estradiol, nor blocked by the estrogen receptor antagonist ICI 182780. The selective estrogen receptor modulator raloxifene (100 nM) neither mimicked nor reversed the effects of estradiol on dendritic branching. Western immunoblotting for the alpha and beta subtypes of estrogen receptor revealed the presence of alpha, but not beta, estrogen receptors in our hippocampal cultures. There is growing recognition of the effects of 17 beta-estradiol on neuronal development and physiology, with implications for brain sexual dimorphism, plasticity, cognition, and the maintenance of cognitive function during aging. The role of estradiol in hippocampal neuronal differentiation and function has particular implications for learning and memory. These data support the hypothesis that 17 beta-estradiol is acting via alpha estrogen receptors in influencing hippocampal development in vitro. Raloxifene, prescribed to combat osteoporosis in post-menopausal women, is a selective estrogen receptor modulator with tissue-specific agonist/antagonist properties. Because raloxifene had no effect on dendritic branching, we hypothesize that it does not interact with the alpha estrogen receptor in this experimental paradigm.