Estrogen receptors are widely distributed in the hippocampus as shown on the figure above. Many estrogenic effects are mediated by these nuclear receptors which are regulated by their ligands. However, "non-genomic", so called rapid effects, have also been described. Estradiol is not mediated in the classical way by ERalpha or ERbeta, via membrane-bound estrogen receptors or other yet unknown mechanisms. Estrogen signalling in the hippocampus is far from being understood.

Role of hippocampus-derived versus gonad-derived estradiol

As gonads are the main sorce of sexual steroids, namely testosterone and estrogen, effects of theses steroids were predominantly attributed to an endocrine regulation by which estradiol reaches its target via plasma. Thus, estrogenic effects in the brain were considered to result from estrogen originating from the gonads. However, a new picture emerged when estrogen synthesis was shown to take place in the hippocampus itself, even more as it was demonstrated that estrogen concentrations in the hippocampus are considerably higher than physiological serum levels. With regard to hippocampal estrogen synthesis the question arises: Which effects are caused by gonad-derived and which ones by hippocampus-derived estrogens? In other words: Which effects are caused by paracrine and which by endocrine regulation?

 Indirect estrogenic effects

Estrogenic effects in the hippocampus are also mediated by projections from subcortical structures to the hippocampus such as the mediane raphe and the submammillary diagonal band (MSDB). The underlying mechanisms of indirect actions on the hippocampus apparently differ substantially from those of direct effects of estrogen locally produced in the hippocampus. While endogenous estrogen acts on hippocampal neurons by inducing the synthesis of synaptic proteins, indirect effects alter network activity of hippocampal neurons, which in turn results in morphological changes.

Estrogen-induced synaptic plasticity

Estrogen regulates the formation of synapses and the expression of corresponding synaptic proteins, such as synaptophysin and spinophilin and synaptopodin. We have shown, that hippocampal synapses depend on hippocampal estrogen synthesis. This was demonstrated by pharmacological inhibition of estradiol synthesis and by using siRNA against steroid metabolites in vitro. Ongoing experiments will show whether suppression of estradiol synthesis in the hippocampus of animals will result in similar effects and will result in deficiencies in learning and memory as the hippocampus is closely related to these specific functions.

Classical parameters of neuroprotection are proliferation, apoptosis and axon length. Axon outgrowth is associated with the expression of GAP43 as shown on the picture on the left. We and others have shown that estradiol is anti-apoptotic and induces axon outgrowth. In this context, the question arises whether endogenous estradiol synthesis would be a target for therapeutical strategies. After brain injury, for instance, in the course of epileptic seizures, endogenous estradiol synthesis is downregulated and we ask, wether re-filling of estrogen stores in the hippocampus could be a therapeutical approach.