COBRE: UND: TACHYKININ MODULATION OF EPILEPSY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Epilepsy is one of the most prevalent neurological diseases in the USA, currently affecting more than 2.5 million individuals. The currently available antiepileptic drugs, while somewhat effective, have side effects and target a limited number of mechanisms. Exploring novel mechanisms or strategies to treat epilepsy is still an arduous task. The tachykinin family of neuropeptides that include substance P, neurokinin A and neurokinin B are proconvulsant. However, the cellular and molecular mechanisms whereby tachykinins exert epileptogenic activities are essentially unknown. We have strong preliminary data demonstrating that tachykinins dramatically increased glutamate release at multiple synapses of the hippocampus by inhibiting the delayed rectifier K+ channels at presynaptic terminals. With knock-out mice and pharmacological approaches, we have also shown that the activities of phospholipase C and protein kinase C were fully, whereas intracellular Ca2+ release was partially required for substance P-induced increases in glutamate release. We also demonstrated that tachykinins significantly increased seizure activities in a picrotoxin-induced seizure model using hippocampal slices. The objective of this project is to determine the detailed cellular and molecular mechanisms underlying tachykinin-induced increases in glutamate release and epileptogenic activities. We will test the hypothesis that tachykinin-mediated increases in glutamate release are responsible for their epileptogenic activities. Specific Aim 1 will identify the detailed ionic mechanisms by which tachykinins facilitate glutamate release. We will identify the subtype of the delayed rectifier K+ channels involved. Specific Aim 2 will identify the signal transduction mechanisms underlying tachykinin-mediated facilitation of glutamate release. Because our preliminary data indicated that the activity of protein kinase C was essential, we will determine the involved isoform of protein kinase C in tachykinin-induced increases in glutamate release. Specific Aim 3 will determine the roles and mechanisms of tachykinins in seizures. We will measure seizure-induced increase in the release of tachykinins to determine the roles of endogenously released tachykinins in seizure generation. We will also use the picrotoxin-induced seizure model in hippocampal slices to identify the signal transduction mechanisms underlying tachykinin-induced facilitation of seizure activities.