The overall objective of this project is to understand the function of the various morphological types of neurons in the cerebral cortex in normal and epileptic animals. Light and electron microscopic as well as immunocytochemical methods will be used to analyze the cellular changes in experimental models of epilepsy. Previous morphological studies from this laboratory have demonstrated that GABAergic, aspinous and sparsely-spinous stellate neurons are preferentially lost at epileptic foci which were created in monkeys by alumina gel. Preliminary quantitative and qualitative data indicate a similar loss of these neurons in another model of epilepsy, the isolated cortical slab. Neurons in the isolated slabs display epileptiform activity following stimulation, and those at the edges display a severe loss of axosomatic, symmetric synapses which are probably GABAergic. Immunocytochemical methods for the localization of glutamate decarboxylase (GAD), the synthesizing enzyme for GABA, will be used to test this notion that was obtained from preliminary quantitative ultrastructural data. If these studies indicate a preferential loss of GABAergic, inhibitory synapses in the isolated cortical slabs, a study will be made to examine the development of these morphological changes to determine their temporal sequence. This study will attempt to link the GABA neuron loss with the onset of seizure activity. An additional model of epilepsy, the gerbil, also will be analyzed with immunocytochemical and quantitative ultrastructural methods. A major advantage of this model is that it occurs naturally without the introduction of exogenous agents to the brain with concomitant glial scars. Together, these studies will attempt to determine the role of GABAergic, inhibitory neurons in epileptic activity and provide functional morphological data for understanding cellular mechanisms of epilepsy. Such information is vital for the development of new therapeutic drugs for the nearly two million Americans with epilepsy.
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