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We have previously reported that in vivo de-polymerization of F-actin filaments induces acute and chronic seizures in mice and rats. On these basis, we have investigated the effect of latrunculin A microdialysis in the mice hippocampus on seizure patterns, F-actin filaments and NMDA receptors. Latrunculin A (8 g/ml) was perfused for three consecutive days into the mice hippocampus using microdialysis probes with continuous EEG and video monitoring. After microdialysis experiments, F-actin depolymerization and synaptic and extrasynaptic NR1 protein levels were investigated. Intrahippocampal latrunculin A microperfusion induced partial seizures during the third day of perfusion, and the animals started showing spontaneous partial seizures one month after treatment. Increased levels of extracellular glutamate via microdialysis probes induced seizures in pre-treated mice. F-actin levels were significantly decreased, while NMDA receptor density increased both in synaptic and non-synaptic locations. These results support the hypothesis that actin disruption might be not just a consequence but also a possible cause of epileptic seizures. Actin depolymerization-induced seizures are related to an increase in synaptic and extrasynaptic NMDA receptors and to changes in the extracellular environment. We propose a new experimental model of epilepsy in mice which has been shown to be useful in the study of the biochemical changes that may lead to chronic seizures, and a new method for testing the efficacy of novel antiepileptic drugs in chronic animals.