Complex partial seizures are the most common type of epileptic syndrome and the most drug resistant. Kindling is a model of complex partial seizures. The long-term objective of this research is to determine the membrane mechanisms underlying the long-lasting changes in the basolateral amygdala resulting from kindling-induced epileptogenesis. We have shown that the kindling profound long-lasting changes occur in metabotropic glutamate receptor (mGluR)-mediated responses in the amygdala. We will define the subtypes of mGluRs and their coupled second messenger effectors that are altered in kindling and test the hypothesis a) that mGluRs affecting kindling-induced bursting are different from those modifying epileptiform bursting in acute models of epilepsy and b) that the changes within mGluR subgroups recorded in kindled neurons are mediated through specific mGluR subtypes. We will use amygdala brain slice preparations from control animals and animals kindled in vivo using intracellular sharp and whole cell patch electrode recording and antisense oligodeoxynucleotide technology (ODN) to address the following specific aims: 1) Characterize the second messenger effectors of the mGluR-mediated responses that have been found to be altered in kindled neurons. 2) Compare pharmacological agonists and antagonists of the subtypes of mGluRs modifying epileptiform bursting in kindled neurons with those affecting the induction and maintenance of epileptiform bursting in acute models of epilepsy. 3) Analyze using anti-sense ODNs the specific subtypes of mGluR underlying mGluR agonist-induced responses, the induction and maintenance of epileptiform bursting in acute models of epilepsy, and epileptiform bursting in kindled neurons. Elucidating the subtypes of mGluRs and their respective second messenger effectors and identifying agonists and antagonists of mGluRs which modify epileptiform bursting in acute models of epilepsy and in kindling will enhance our understanding of the mechanisms underlying epileptogenesis in the amygdala and ultimately to evolve more effective therapies for the treatment of complex partial seizures.
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