Glial cells are critical regulators of nervous system function and may play a central role in the initiation and propagation of seizures, as well as in the long-term pathological and physiological cellular changes associated with chronic epilepsy. We have shown that glial cells are capable of extensive intercellular signaling, as well as bi-directional communication with neurons. To investigate the function of glial cells in epileptic tissue and the broad hypothesis that bi-directional glial- neuronal signaling plays a role in epilepsy, we will test the following specific hypotheses: 1) Glial cells from specific regions of human epileptic temporal lobe have different intrinsic Ca2+ signaling properties, patterns of intercellular communication, and responses to neurotransmitters which correlate with the epileptogenicity of each region as defined by the the pathological substrate (hippocampal sclerosis vs. neocortical lesion) and as evidenced by in vivo electrophysiology, in vivo microdialysis studies, in vitro electrophysiology, and microanatomical studies. 2) Glial cell Ca2+ signaling responses are correlated with other physiological parameters including membrane potential, cell morphology, and expression of proteins such as GFAP and A2B5. 3) Glial cells from these different regions have different effects on the excitability of neighboring neurons which correlate with the epileptogenicity of the region as described above. 4) Glial cells from different regions of the epileptic temporal lobe release different amounts of glutamate and GABA in response to stimuli which increase [Ca2+]i. 5) Glial cell intercellular Ca2+ waves are associated with the release and extracellular messenger that directly affects neuronal excitability 6) Glial cells from different regions of the temporal lobe of the intrahippocampal kainate rat model of epilepsy have differences in Ca2+ signaling, release of amino acids, and interactions with neighboring neurons which can be correlated with those seen in human tissue. We will grow glial cells in culture from the human epileptic hippocampus, entorhinal cortex, neocortex, temporal lobe glial tumors, and from tissue immediately surrounding the tumors, and we will co-culture glia from each region with clonal GT1 and IMR neurons. We will quantify spontaneous cellular activity, as well as responses to glutamate, GABA, ATP, mechanical stimulation, and osmotic stimulation using quantitative fluorescence video imaging techniques, patch clamp techniques, time-lapse phase contrast video recordings, and immunofluorescence staining. We will quantify glial glutamate and GABA release using high pressure liquid chromatography. We will perform parallel studies on glia from the intrahippocampal kainate rat model. Glial cell signaling pathways may represent a pharmacologically accessible target for therapeutic modulation of neuronal excitability. An increased understanding of glial cell signaling mechanisms may lead to the development of new strategies for the treatment of epilepsy.
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