Neuronal migration disorders resulting in cortical dysplasia, microgyria, and hectrotopias are associated with intractable seizure disorders in humans. We have used the rat freeze lesion model to examine neural mechanisms underlying hyperexcitability in dysplastic cortex. Proposed studies will combine optical imaging and whole-cell voltage-clamp techniques to test specific hypotheses about mechanisms that control excitability in the dysplastic cortex. These mechanisms are alterations in N-methyl-D-aspartate receptors (NMDARs) in local horizontal pathways and remodeling of GABAergic networks. Experiments will investigate if the enhanced spread of voltage sensitive dye signals we observed in slices from dysplastic cortex is due to an increased contribution from NMDARs in intracortical horizontal pathways. It will be determined if blockage of NMDAR activation changes the spatial and temporal extent of cortical circuit activation. We will examine if NR2B subunit containing NMDARs in lesioned cortex confer hyperexcitability through the prolongation of excitatory postsynaptic currents. It is hypothesized that NMDAR EPSCs are prolonged in dysplastic cortex and resemble those seen at earlier stages of development in normal neocortex. Anatomical studies will determine if there are changes in the number or extent of axon collaterals forming horizontal connections. We will also determine the site of origin and pattern of spread of depolarizing GABA waves in dysplastic neocortex. It is hypothesized that reorganization of GABA-ergic networks in dysplastic cortex will result in different patterns and rates of propagation. We will delineate the site of origin and pattern of spread of depolarizing GABA waves in dysplastic neocortex. It is hypothesized that a propagating wave of potassium results in spreading changes in intracellular chloride due to activity of potassium-coupled chloride cotransporters. Changes in extracellular potassium and application of transport blockers are predicted to change or block propagation. Glial cells are coupled by gap junctions and participate in spatial buffering of potassium. Disruption of gap junctions is predicted to change or block propagation. These studies will provide important new information about NMDA and GABA receptors in neocortex. They will also contribute to our understanding of the functional changes at both the cellular and circuit level, responsible for the intrinsic hyperexcitability of dysplastic cortex in the freeze lesion model.
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