Temporal lobe epilepsy is the most common form of epilepsy in adults and one of the most difficult types to treat. The broad long-term objective of the proposed project is to help reveal the mechanisms of temporal lobe epilepsy so that more effective treatments and preventative strategies can be developed. Specifically, we propose to develop a treatment that will block injury-induced axon sprouting and test a hypothesis of temporal lobe epileptogenesis. It has been hypothesized that epileptogenic injuries trigger axon reorganization (mossy fiber sprouting), which creates a positive-feedback circuit between dentate granule cells that lowers seizure threshold. To test this hypothesis we will develop a treatment to block mossy fiber sprouting (Specific Aim 1). Rats that have experienced pilocarpine-induced status epilepticus will be surgically implanted with a pump and cannula to focally infuse agents into one hippocampus. Inhibitors of calcineurin, a calcium-activated phosphatase, will be tested. After 28 days of continuous infusion, mossy fiber sprouting will be measured using Timm-staining and design-based stereological methods, and synaptic reorganization will be measured with electron microscopy. Agent-infused hippocampi will be compared to uninfused contralateral hippocampi and vehicle-infused controls. The treatment duration sufficient to block mossy fiber sprouting and the permanence of the block will be determined by varying the duration of infusion or the survival period following infusion, respectively (Specific Aim 2). To test whether mossy fiber sprouting contributes to epileptogenesis the septal and temporal parts of both hippocampi will be treated to maximally suppress mossy fiber sprouting, and then rats will be monitored for spontaneous seizure activity using video-taping and EEG recording (Specific Aim 3). ? ? ?
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