Disruptions in neuronal activity are known to occur in and around a wide variety of malformations in the infant brain. Recurrent seizures often originate from these malformed lesions. The goal of this research program is to further our understanding of how localized interruptions in neuronal activity may contribute to the formation of epileptic foci. For the first time, our laboratory has shown that a life long epilepsy is produced when neuronal activity is abolished by local infusion of the voltage gated sodium channel antagonist, TTX, into the immature hippocampus. EEG recordings have shown that the infused hippocampus is an epileptic focus and abnormal synchronized network discharges are recorded in area CA3 of hippocampal slices taken from these animals. Experiments have examined the possibility that CA3 network hyperexcitability is the result of sprouting and hyperinnervation of CA3 pyramidal cells by local recurrent excitatory axon collaterals. However, results do not favor this hypothesis. On the other hand, results demonstrate a significant increase and alterations in the expression of subunits for both AMPA and NMDA receptors. In proposed experiments, this new model of early-onset epilepsy will be further characterized. Included, are studies demonstrating that TTX-infusion in developing neocortex can also produce epileptic loci. The remaining experiments focus on a single unifying hypothesis that chronic activity blockade results in dramatic changes in subunit composition of glutamatergic synapses and that these changes result in unusually large and prolonged AMPA and NMDA receptor mediated EPSPs that contribute to synchronized network discharging and the chronic epilepsy observed in these animals. Planned electrophysiolgical and biochemical experiments will characterize alterations in AMPA and NMDA receptor mediated synaptic transmission during activity blockade. Intrahippocampal infusion of AMPA and NMDA receptor antagonists is expected to produce similar changes at glutamatergic synapses and epilepsy. Since there are so few animal models of early-onset epilepsy, the studies proposed here offer a unique opportunity to further an understanding of the biological origins of seizure disorders in infancy.
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