Chronic temporal lobe epilepsy is often accompanied by cognitive dysfunction such as declarative memory deficit. In order to find promising strategies to address these deficits, we study fundamental molecular mechanisms of learning and memory such as long-term potentiation (LTP) and long-term depression (LTD). These are long-lasting changes of synaptic strength due to the history of prior neuronal activity. By using long-term extracellular recording techniques, we asked how chronic epileptic seizures influence NMDA receptor-dependent synaptic plasticity in the hippocampus of the rat pilocarpine-induced status epilepticus model. In the lateral perforant path of the dentate gyrus, NMDA receptor-dependent LTP induced by a modified theta-burst stimulation was significantly reduced in pilocarpine-treated rats. In contrast, LTP in the medial perforant path was unaffected following status epilepticus. On the other hand, we found an unexpected increase of NMDA receptor-dependent LTP in the CA1 region. However, NMDA receptor-dependent LTD was unaltered at these synapses. Therefore, we asked whether this discrepancy is due to a differential alteration of the most important NMDA receptor subtypes NR2A and NR2B. We found that application of low micromolar zinc (10 mM), which primarily modulates NR2A, virtually abolished LTP in controls, whereas in epileptic rats significant LTP was still observed. At a higher zinc concentration (100 mM), LTP was inhibited in both groups. Moreover, in pilocarpine-treated rats, significant LTD was induced under these conditions. Therefore, more specific NMDA receptor antagonists were employed to discriminate between NR2A- and NR2B-dependent LTP. When NR2B was inhibited by Ro 25-6981, LTP remained inducible in controls, but was completely lost after status epilepticus. On the other hand, LTP was not altered by predominant NR2A blockade (NVP-AAM077) in controls, but was significantly impaired in pilocarpine-treated rats albeit incompletely. These results suggested a dominant role of NR2B in LTP induction in epileptic rats which may be caused by post-transcriptional and/or post-translational modification of these NMDA receptor subtypes. In conclusion, status epilepticus leads to persistent changes of various forms of synaptic plasticity in the hippocampus. These changes could be in part accountable for cognitive impairment seen in many patients. A more precise understanding of the underlying mechanisms will be essential to develop new therapeutic strategies.