Epilepsy is a common and potentially disabling disorder characterized by abnormal electrical discharges in the brain and recurrent motor seizures. Despite a great deal of information on the nature of the electrical discharges which characterize epileptiform activity, little is known about the synaptic mechanisms which underlie the transition from the normal to the epileptic state. The goal of this investigation is to determine the cellular processes which underlie the development of epileptiform activity. An experimental model which induces electrical activity similar to that observed in epilepsy is provided by the repetitive tetanic stimulation of certain brain structures (eg amygdala, hippocampus), designated as kindling. Kindling is generally obtained in vivo, but more recently has been studied in slices of limbic structures. We proposed to study the changes in synaptic transmission and receptor sensitivity which accompany the development of epileptiform activity in the hippocampus using an in vitro equivalent of the kindling model of epilepsy. This in vitro model allows the maintenance of stable extra- and intracellular recording during the repetitive application of electrical stimuli to selected pathways in the hippocampal slice. The effects of electrical kindling will be examined on the time course of changes in synaptic transmission and the sensitivity of hippocampal neurons to agonists of those neurotransmitter receptors which play key roles in excitatory and inhibitory transmission, and synaptic plasticity. To monitor global changes in synaptic transmission and drug sensitivity produced by electrical kindling of specific pathways in the hippocampus, intracellular recording of synaptically and ionophoretically-evoked responses will be used. Current- and voltage-clamp recording will be employed to examine the biophysical changes in synaptic transmission and agonists responsiveness produced by kindling. Ionophoretic mapping experiments will be performed to determine which neurotransmitter receptors are affected by kindling, and to follow the topographic spread of these changes across the dendritic fields of pyramidal neurons. This data will be cerrelated with an examination of the effects of kindling on non-tetanized synaptic inputs to reconstruct the cellular physiologic and pharmacologic events that accompany kindling at the site of stimulation, and at other regions of the target neuron. The efficacy of anticonvulsant drugs and norepinephrine to modulate the development and expression of kindling-induced changes in synaptic transmission and neurotransmitter sensitivity will be examined to better understand the mechanisms of action of clinically therapeutic drugs. The results of this study should provide a better understanding of the cellular mechanisms which underlie the development and expression of limbic seizures, and may well have relevance to clinical epilepsy.
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