While much research has focused on the study of seizures in the mature nervous system, comparatively few attempts have been made to understand epileptogenesis in the developing brain. Numerous clinical and experimental studies support the notion that seizures early in life arise in ways that are different from those in adulthood. It is generally agreed that during certain critical periods in development the immature nervous system is unusually susceptible to seizures. The research proposed here is based on the observation that the CA3 subfield of slices taken from 1-2 week old rat hippocampus have a marked capacity to undergo electrographic seizures. Results suggest that age-dependent alterations in recurrent excitatory synaptic transmission contribute to differences in seizure susceptibility. Indeed, we propose that CA3 pyramidal cell recurrent axon collaterals and synapses undergo substantial remodeling during brain maturation. Early formed synapses appear to be replaced by a different complement of synapses in adulthood. Differences in synaptic physiology are likely to underlie enhanced seizure susceptibility in early life. Therefore, experiments are proposed that will directly compare local circuit excitation in immature (day 10-15) and mature (day 40-50) rat hippocampus. Electrophysiological properties of recurrent excitatory synapses will be examined in detail. We also plan to determine if neonatal amygdala kindling alters the recurrent collateral remodeling that normally takes place in early life. If CA3 network remodeling is a use-dependent process, then abnormal activation of hippocampal networks during kindling may lead to the persistence of excitatory synapses that would normally be eliminated with age. Such alterations in network development could conceivably underlie seizures in adulthood. Finally, recurrent excitatory synapse formation in slice cultures will be studied. Ultimately, these experiments will attempt to identify fundamental neurobiological processes that underlie recurrent excitatory synapse formation and selection. Taken together these multi- disciplinary studies are focused on understanding the ontogeny of local excitatory networks in hippocampus, how they contribute to seizures in early life, and whether experience-dependent modification of network development underlies some forms of temporal lobe epilepsy.
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