Several intrinsic and synaptic mechanisms have been proposed to play an important role in cortical epileptogenesis; for example, local synaptic interactions are thought to be crucial for synchronization of epileptiform bursts. Most in vitro research has dealt with acute, convulsant-induced epileptiform bursting; the proposed in vitro studies in the dentate gyrus will use a chronic model of epilepsy, the kainate-treated rat. Intravenous or intraventricular injections of kainate are known to cause lesions of hippocampal pyramidal cells that ultimately lead to epileptiform activity of the remaining neurons within a few weeks after the injection. Based on previous research, the main hypothesis to be tested is that kainate-induced neurodegeneration in the CA3 area leads to mossy fiber sprouting and the formation of recurrent excitatory synapses, which in turn are responsible for epileptiform bursting by the dentate granule cells. Two other related hypotheses to be tested are that kainate-induced epileptogenesis is due to a decrease in recurrent inhibition and that an increased voltage-dependent Ca2+ conductance causes epileptogenesis. Single and dual intracellular recordings will be made from granule cells in hippocampal slices containing the isolated dentate gyrus. All electrophysiological results will be correlated with quantitative data from Nissl- and Timm's-stained tissue to evaluate neuronal destruction in Ammon's horn and mossy fiber sprouting in the dentate gyrus. The hypotheses on local synaptic interactions and Ca2+ conductance are not mutually exclusive; on the contrary, alterations in neuronal properties and synaptic interactions both can lead to epileptic activity. However, the hypothesis that the formation of this local synaptic circuit could be an initial consequence of a lesion that leads to epileptogenesis has not been examined extensively. The proposed experiments will provide fundamental information about the possible contributions of new synaptic interactions, as well as intrinsic conductance mechanisms, to epileptogenesis. Our long-term objective is to understand how cortical destruction and degeneration alter the intrinsic properties and local synaptic interactions of neighboring cortical neurons.
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