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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022373-17
Application #
6624319
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Fureman, Brandy E
Project Start
1986-04-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
17
Fiscal Year
2003
Total Cost
$272,650
Indirect Cost
Name
University of Alabama Birmingham
Department
Neurosciences
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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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