The long-term consequences of brain injury are a critical problem in clinical neuroscience. One important example is how excitotoxic neurodegenerative lesions, such as damage to hippocampal neurons that occurs with prolonged status epilepticus, can ultimately lead to chronic epilepsy. The proposed studies use acute hippocampal slices from kainate-treated rats to determine how status epilepticus leads to the reorganization of local synaptic circuits in the dentate gyrus and CA1 areas of the hippocampus. Whole cell patch clamp analyses of synaptic currents, focal microstimulation of hippocampal neurons with photolysis of caged glutamate, and dual recordings will be combined with anatomic techniques to test specific hypotheses about changes in recurrent excitation and inhibition.
We aim to determine whether status epilepticus is followed by a progressive development of new abnormal synaptic circuits that contribute to changes in hippocampal seizure susceptibility. Although our primary focus will be to evaluate more rigorously whether new recurrent excitatory circuits are formed in the hippocampus after status epilepticus, and to understand how the putative increase in density of these circuits alters the properties of hippocampal networks, the applicants will also examine hypothetical changes in local inhibitory circuits. The applicants aim to focus on the progressive nature of the synaptic reorganization of the hippocampus as a model for time-dependent changes in cortical networks that may occur throughout the temporal lobe and other neocortical areas after neurodegenerative brain injuries.
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