Temporal lobe epilepsy is a common form of epilepsy that frequently becomes resistant to anticonvulsant drugs and is sometimes progressive. The evolving physiological and neuropathological processes that eventually made chronic susceptibility to recurring seizures, development of anticonvulsant drug resistance, and progression to intractable temporal lobe epilepsy are not well understood are not well understand. Limbic kindling has been studied as a model of temporal lobe epilepsy because kindled seizures have many features that resemble human partial complex seizures arising from the temporal lobe. Repeated brief seizures evoked by kindling, which gradually increase susceptibility to additional seizures and eventually induce spontaneous seizures in the absence of an initial participating injury, provide an opportunity to study how repeated seizures may contribute to intractable temporal lobe epilepsy. In the dentate gyrus, kindling induces neuronal loss and mossy fiber sprouting, which are also observed in the human epileptic temporal lobe. Seizure- induced cellular alterations such as neuronal loss and formation of recurrent circuits formed by sprouted mossy fibers could increase susceptibility to additional seizures by modifying the balance of excitation and inhibition of hippocampal pathways. Recent studies in our lab have revealed that the development of spontaneous seizures during kindling coincides with loss of inhibition in the dentate gyrus. The proposed experiments. utilize anatomical and physiological methods to investigate the relationship between repeated seizures, reduction of inhibition, and chronic seizure-induced cellular alterations in the dentate gyrus that contribute to spontaneous seizures and intractable epilepsy. The results of these studies will be important for understanding how poorly controlled seizures in people may contribute to recurring seizures and intractable temporal lobe epilepsy.
