Intractable seizure disorders in humans are often associated with cortical dysplasia, microgyria, and heterotopias resulting from neuronal migration disorders. We have used the rat freeze lesion model to examine neural mechanisms underlying hyperexcitability in focal cortical dysplasia. Our previous studies have shown an involvement of N-methyl-D-aspartate (NMDA) receptors in generation of epileptiform discharges in slices from freeze lesioned animals and have identified changes in potassium channel expression in glial cells. Proposed studies will use whole-cell voltage-clamp recordings from neurons and glial cells to test specific hypotheses about the role of glial potassium currents and glutamate transporters in control of excitability in the dysplastic cortex. Glutamate transporters are important for regulating glutamate levels in the neocortex. It is hypothesized that increases in extracellular glutamate, due to alterations in glutamate transporters, lead to activation of NMDA receptors in dysplastic cortex. It is also hypothesized that changes in potassium channels in glia result in an altered ability to buffer extracellular potassium. Experiments will investigate if decreases in glutamate transporter function make synaptic responses from neurons in dysplastic cortex more sensitive to transporter inhibition than cells from sham operated controls. It will be determined if alterations in transporter function are proconvulsant and if such effects are mediated by NMDA receptors. We will also determine if extracellular glutamate is chronically elevated in dysplastic cortex and if this results in tonic activation of NMDA receptors and a depolarization of neurons. The source of increased extracellular glutamate will be determined by testing the role of action potential dependent release, glutamate transport and cystine-glutamate exchange. Finally, we will determine if the changes in glial ion channel expression we have described are associated with alterations in glutamate transporter current alterations. It is hypothesized that synaptically evoked glutamate tranporter currents in astrocytes differ in their kinetic properties and are reduced. These studies will provide important new information about regulation of extracellular glutamate and .tonic NMDA receptor activation in neocortex. New insights into the role of glutamate transporters in development and regulation of epileptiform activity will be forthcoming. These studies will also increase our understanding of the contribution of glial cells to the intrinsic hyperexcitability observed in freeze-induced focal cortical dysplasia.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Developmental Brain Disorders Study Section (DBD)
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Fureman, Brandy E
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University of Alabama Birmingham
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Albertson, Asher J; Williams, Sidney B; Hablitz, John J (2013) Regulation of epileptiform discharges in rat neocortex by HCN channels. J Neurophysiol 110:1733-43
Albertson, Asher J; Yang, Jianming; Hablitz, John J (2011) Decreased hyperpolarization-activated currents in layer 5 pyramidal neurons enhances excitability in focal cortical dysplasia. J Neurophysiol 106:2189-200
Skov, Jane; Andreasen, Mogens; Hablitz, John J et al. (2011) Baclofen and adenosine inhibition of synaptic transmission at CA3-CA1 synapses display differential sensitivity to K+ channel blockade. Cell Mol Neurobiol 31:587-96
Mathew, Seena S; Hablitz, John J (2011) Presynaptic NMDA receptors mediate IPSC potentiation at GABAergic synapses in developing rat neocortex. PLoS One 6:e17311
Hablitz, John J; Yang, Jianming (2010) Abnormal pyramidal cell morphology and HCN channel expression in cortical dysplasia. Epilepsia 51 Suppl 3:52-5
Hablitz, John J; Mathew, Seena S; Pozzo-Miller, Lucas (2009) GABA vesicles at synapses: are there 2 distinct pools? Neuroscientist 15:218-24
Mathew, Seena S; Hablitz, John J (2008) Calcium release via activation of presynaptic IP3 receptors contributes to kainate-induced IPSC facilitation in rat neocortex. Neuropharmacology 55:106-16
Campbell, Susan L; Hablitz, John J (2008) Decreased glutamate transport enhances excitability in a rat model of cortical dysplasia. Neurobiol Dis 32:254-61
Mathew, Seena S; Pozzo-Miller, Lucas; Hablitz, John J (2008) Kainate modulates presynaptic GABA release from two vesicle pools. J Neurosci 28:725-31
Campbell, Susan L; Mathew, Seena S; Hablitz, John J (2007) Pre- and postsynaptic effects of kainate on layer II/III pyramidal cells in rat neocortex. Neuropharmacology 53:37-47

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