Memory impairment is a common consequence of epileptic seizures. The hippocampal formation is particularly prone to seizure-induced amnesia due to its prominent role in mnemonic processes. We used the isolated CA1 slice preparation to examine effects of seizure-like activity on hippocampal plasticity, long-term potentiation (LTP) and long-term depression (LTD). Repeated spontaneous ictal events, generated in the presence of antagonists of GABA_A receptor function, led to a stepwise erasure of LTP (termed spontaneous depotentiation, SDP). SDP could be initiated at various stages of LTP consolidation (tested up to 120 min following the induction of LTP). Renewed tetanic stimulation re-established LTP. SDP was remarkably specific: baseline transmission and other forms of hippocampal plasticity, i.e., Ca²⁺-induced LTP and two forms of LTD (DHPG- and LFS-mediated) were not affected by the same type of seizure activity. Group I mGluR activation was necessary for the induction of SDP: SDP was blocked in the presence of the group I mGluR antagonist 4-CPG. The mGluR1 antagonist LY367385 blocked about 80%, the mGluR5-specific antagonist MPEP blocked about 30% of SDP. Most efficient implementation of SDP was observed during seizures in the combined presence of the group I mGluR agonist DHPG and the GABA_A antagonist Bicuculline. During DHPG-induced seizure activity alone, however, LTP was not reversed. Tonic cell depolarization of CA1 pyramidal cells was identified as a critical mechanism underlying SDP: (a) significant depolarization was present in CA1 pyramidal cells during the DHPG+Bic protocol of depotentiation; (b) hyperpolarization by negative current injection prevented intracellular SDP in the depotentiating seizure protocol of DHPG+Bic; (c) depolarization by positive current injection led to selective intracellular SDP in the non-depotentiating seizure protocol of DHPG.