LOCAL INTERACTIONS BETWEEN HIPPOCAMPAL NEURONS

描述（研究者摘要）：虽然相当可观

DESCRIPTION (Investigator's Abstract): Although considerable information is available about the mechanisms underlying seizure generation, the cellular basis of chronic epileptogenesis is not understood. Both synaptic and nonsynaptic mechanisms are likely to contribute to the hypersynchronization characteristic of seizures in temporal lobe epilepsy. The kainate treated rat will be used as an animal model to study how these mechanisms of neuronal communication participate in the seizures associated with temporal-lobe epilepsy. Behavioral, electrophysiological and anatomical studies will be undertaken 2-3 mo after kainate treatment, when the animals show many of the clinical features of temporal-lobe epilepsy. Using both in vivo and in vitro electrophysiological recording with subsequent anatomical analysis in the same animal, we will evaluate whether synaptic reorganization (e.g., altered recurrent excitation and/or inhibition) and/or changes in nonsynaptic mechanisms contribute significantly to hippocampal epileptogenesis. The two hypotheses to be tested are-that new recurrent excitatory circuits and/or enhanced non-synaptic mechanisms contribute to or mediate the increased hippocampal seizure susceptibility of temporal-lobe epilepsy. Chronic in vivo recording of field potentials from the dentate granule cells and simultaneous video monitoring will be used to evaluate hippocampal seizure susceptibility in freely-behaving kainate-treated rats. Synaptic inhibition will be evaluated in vivo with paired-pulse perforant-path stimulation. "Spontaneous" interictal spikes and hippocampal seizures will also be assessed in vivo. lntracellular and extracellular recordings from dentate granule cells in hippocampal slices will then be undertaken to determine cellular alterations in synaptic and nonsynaptic mechanisms from the same kainate-treated rats. Extracellular stimulation, glutamate microapplication, and dual intracellular recordings will be used to evaluate whether changes in recurrent inhibition and/or excitation have increased seizure susceptibility in the dentate gyrus. Similar experiments using high extracellular [K~], low extracellular ICa2+] and bath application of amino acid receptor antagonists will identify the contribution of nonsynaptic mechanisms to epileptogenesis. Other studies on the dentate gyrus of kainate-treated rats before sprouting and of hippocampal- lesioned rats after sprouting will provide additional tests of the hypothesis that synaptic reorganization plays a critical role in damage- induced epilepsy. These in vitro experiments will indicate whether synaptic and nonsynaptic mechanisms chronically alter seizure susceptibility during hippocampal epileptogenesis in the kainate-treated rat. A critical analysis of these issues will provide important new information about the role of these mechanisms in chronic epileptogenesis, which will in turn lead to a better understanding of how to treat temporal-lobe epilepsy.