Many studies have analyzed axonal sprouting and synaptic reorganization of local excitatory circuits in animal models of temporal lobe epilepsy, but relatively little electrophysiological research at the single-neuron level has been conducted on reorganization of local inhibitory circuits during epileptogenesis. Furthermore, the dynamic properties of these reorganized circuits during repetitive synaptic activation, as expected during the onset of hippocampal seizures, are relatively unknown The general questions to be addressed in the proposed experiments are what are the short- and long-term alterations in local inhibitory circuits after status epilepticus, and does synaptic depression during repetitive activation of these circuits contribute to seizure propagation during chronic epileptogenesis? The proposed experiments will use hippocampal slices from rats with kainate-induced epilepsy to determine how loss of synaptic input and subsequent synaptic reorganization after status epilepticus leads to changes in local inhibitory circuits in the dentate gyrus and the CA1 area Inhibitory circuits in these two hippocampal areas appear to be different after SE The experiments will address the following specific questions (1) Does axonal sprouting of principal neurons in the hippocampus (e g, dentate granule cells and CA1 pyramidal cells) lead to formation of functional excitatory synapses on inhibitory interneurons? (2) Do interneurons sprout axon collaterals, and form new inhibitory synapses with principal neurons? (3) How does repetitive activation of local inhibitory circuits alter transmission through this network, and are these areas of the hippocampus abnormally sensitive to repetitive activation at periods after status epilepticus when recurrent spontaneous seizures occur? Aim 3 will utilize frequencies of repetitive stimulation that simulate the patterns of synaptic activation observed at the onset of chronically recorded electrographic seizures in rats with kainate-induced epilepsy These experiments aim to provide increased understanding about the reorganization of inhibitory circuits that may contribute to temporal lobe epilepsy, and how activity-dependent depression of local inhibitory circuits may promote the spread of epileptic seizures The systems to be investigated are prime targets for therapeutic intervention to prevent seizures in people with intractable temporal lobe epilepsy.
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