Estrogen exerts neuroprotective activity under different experimental conditions through classical nuclear receptors, but mainly receptors expressed at the cell surface. Transducing mechanisms activated by these membrane estrogen receptors in the brain have been intensely investigated and, among others, interaction with G-protein coupled, metabotropic glutamate (mGlu) receptors has been considered. Besides mediating physiological estrogen functions, such as regulation of hormone production or sexual behaviour in the hypothalamus, mGlu receptors, specifically mGlu1 receptor subtype, take part to the protective effect of estrogen in a model of neuronal toxicity induced by β-amyloid peptide. Coupling of estrogen receptor to mGlu1 receptor is supported by co-immunoprecipitation, similar neuroprotective effect induced by either receptor activation, lack of additivity when the two receptors are activated at the same time and prevention of the protective effect when antagonists of the other receptor are used, i.e. reduction of the protective effect of estrogen by the mGlu1 receptor antagonist and vice versa. In addition, the phosphatidylinositol-3 kinase/Akt pathway may represent the common signalling pathway to produce neuroprotection. These data introduce a novel view of the mechanisms underlying the neuroprotective activity of estrogen and open new perspectives also for future pharmacological interventions.