Estrogen: A multifunctional messenger to nigrostriatal dopaminergic neurons

Gonadal steroids affect a wide variety of functions in the mammalian brain ranging from the regulation of neuroendocrine systems and the modulation of behavior to the stimulation of differentiation and plasticity of distinct neuronal populations and circuits. The last decades have also demonstrated that estrogen serves as a neuroprotective factor for distinct neurodegenera tive disorders. Such neuroprotective effects of estrogen are most obvious f or Parkinson's and Alzheimer's disease. Despite this knowledge, little is k nown about the mechanisms and cellular targets by that estrogen might elici t its protective influence. In the past, we have intensively studied the ef fects of estrogen on midbrain dopaminergic neurons which represent the most affected cell population juring Parkinson's disease. These studies were ma inly performed on developing dopaminergic cells and revealed that estrogen is an important regulator of plasticity and function of this neuronal pheno type. Precisely, we found that dopaminergic neurons are direct targets for estrogen and that estrogen stimulates neurite extension/branching and the e xpression of tyrosine hydroxylase, the key enzyme in dopamine synthesis. To gether with other in vivo studies, we might draw the conclusion that estrog en is required for the plasticity and activity of the developing and adult nigrostriatal system. The presence of the estrogen-synthesizing enzyme arom atase within the nigrostriatal system further supports this idea. Surprisin gly, estrogen effects on nigrostriatal cell function are not only transmitt ed by classical nuclear estrogen receptors but also depend on nonclassical estrogen actions mediated through putative membrane receptors coupled to di verse intracellular signaling cascades. In the future, it has to be elucida ted whether nonclassical mechanisms besides genomic actions also contribute to estrogen-mediated neuroprotection in the adult CNS.