We have shown previously that a selective metabotropic glutamate receptor (mGluR) agonist, 1S,3R-1-aminocyclo-pentane-1, 3-dicarboxylate (1S,3R-ACPD), evokes an inward current in CA1 pyramidal neurons of rat hippocampal slices in the presence of K+ channel blockers (). This current has been characterized as a Ca2+-activated nonselective cationic (CAN) current. Using whole-cell patch-clamp recordings and intracellular dialysis, we now have identified the mGluR subtype and the mechanisms underlying the CAN current (ICAN) and report for the first time the presence of a synaptic ICAN in the mammalian CNS. First, we have shown pharmacologically that activation of ICAN by 1S,3R-ACPD involves the group I mGluRs (and not the groups II and III) and a G-protein-dependent process. We also report that ICAN is modulated by the divalent cations (Mg2+, Cd2+, and Zn2+). Second, we have isolated a slow synaptic inward current evoked by a high-frequency stimulation in the presence of K+ channel blockers, ionotropic glutamate, and GABAA receptor antagonists. This current shows similar properties to the exogenously evoked ICAN: its reversal potential is close to the reversal potential of the 1S, 3R-ACPD-evoked ICAN, and it is G-protein- and Ca2+-dependent. Because the amplitude and duration of ICAN increased in the presence of a glutamate uptake blocker, we suggest that this synaptic current is generated via the activation of mGluRs. We propose that the synaptic ICAN, activated by a brief tetanic stimulation and leading to a long-lasting inward current, may be involved in neuronal plasticity and synchronized network-driven oscillations.