Classically, estrogen has multiple actions in the brain via genomic mechanisms which generally take several hours.The present study was designed to examine that whether estrogen regulates glutamatergic transmission and plasticity within minutes and what is the possible mechanisms underlying the estrogen-induced rapid effects in the anterior cingulate cortex (ACC).Immunohistochemistry results revealed that estrogen receptors (ERs) were highly expressed in glutamatergic neurons of the ACC.Whole-cell recording from ACC slices results showed that estrogen enhanced the glutamatergic excitatory postsynaptic currents (EPSCs) in a dose-dependent fashion.However, the affect of estrogen on AMPA and NMDA transmission exhibited an opposite manifestation: NMDA-mediated EPSCs (NMDA-EPSCs) were significantly enhanced; whereas AMPA-EPSCs were remarkably inhibited.The fast onset effect of enhanced NMDA-EPSCs, within 6 minutes bath application of estrogen, lasted for more than 30 minutes (NMDA-LTP).This NMDA-LTP was blocked by ER antagonist (ICI 182780) and was mimicked by E-BSA, a specific agonist of membrane ER.Moreover, the induction of estrogen-induced NMDA-LTP was also prevented by NR2B inhibitor and PKA inhibitor.Taken together, these findings implicate that estrogen has rapid effects on glutamate transmission in ACC neurons.Also, estrogen-induced chemical NMDA-LTP is at least partially mediated by membrane ER.NR2B-PKA pathway may play a critical role in estrogen-induced NMDA-LTP.