[Neuronal plasticity associated with learning and epileptic seizures: LTP and KIP]

Long-term synaptic potentiation (LTP) and kindling-induced potentiation (KIP) are hypothesized to play an important role in spatial learning and kindling development, respectively, and the possible roles of LTP in spatial learning and KIP in kindling development are reviewed in this paper. Blockage of NMDA receptors, protein synthesis inhibition and knockout of alpha-CaMKII gene markedly impaired both LTP-induction and spatial learning, and destruction of the dentate granule cells with colchicine has been reported to result in severe spatial learning deficits. These findings support the hypothesis that spatial learning may depend on the neuronal input from the entorhinal cortex to dentate granule cells via perforant path and LTP-induction at perforant path-dentate granule cell synapses. However, recent studies have revealed that MPC17742, a selective NMDA receptor antagonist, and 1S, 3S-ACPD, the group II metabotropic glutamate receptor agonist, block LTP-induction at perforant path-dentate granule cell synapses, but that those drugs did not prevent rats from spatial learning. Thus, adaptable changes in the dentate granule cell discharge caused by the neuronal information from the entorhinal cortex are necessary, but LTP at perforant path-dentate granule cell synapses is not necessarily requisite for spatial learning. It has been also hypothesized that kindling development might be based on the long-lasting synaptic potentiation (the KIP/kindling hypothesis). Destruction of the dentate granule cells with colchicine retarded kindling development of amygdala or entorhinal cortex has been reported, and repeated induction of LTP at perforant path-dentate granule cell synapses, furthermore, caused anomalous mossy fiber sprouting and facilitated the subsequent kindling development. These results are in accordance with the KIP/kindling hypothesis. However, even when LTP was induced once a day for 20 days, the repeated induction of LTP failed to induce epileptic discharge. We demonstrated that KIP observed in an interictal period faded away gradually during kindling stimulation before epileptic seizures began. Furthermore, rapid kindling at an interstimulus interval of 5 min blocked completely the development of KIP, whereas the afterdischarge prolonged gradually and generalized convulsions were often observed during the late stage of rapid kindling. Thus, LTP and KIP are not indispensable for kindling development, even if LTP facilitate the subsequent kindling development. It should be noted that instead of KIP, the abnormal plasticity essential for kindling development must appear during an transition period from interictal to ictal periods.