As in other tissues, oestradiol acts in the brain by activating several complementary sig¬nalling mechanisms, the best characterized of which is the regulation of gene transcription through classical intracellular ERs (FIG. 2). Classical ERs are transcription factors that have the peculiarity of being activated by a ligand (oestradiol). At present, two main forms of classical ERs — ERα and ERβ — have been identified and cloned30–32. Both receptor forms have a similar structure, with a DNA-binding domain and a ligand-binding domain. Oestradiol binds to the ligand-binding domain and induces the acti¬vation and the homodimerization or heterodimerization of the ER. Subsequently, the ER binds to oestrogen-responsive elements (EREs) in the promoter region of specific genes through the DNA-binding domain, result¬ing in the recruitment of transcriptional co activators and co repressors33. Classical ERs may also regulate gene tran¬scription by acting as transcriptional partners at non-ERE sites, such as activating protein 1 (AP1) sites34. In addition, classical ERs have two activation domains, which allow them to be regulated by kinases activated by the signalling pathways of several growth factors, such as insulin-like growth factor 1 (IGF1)35,36.