Neuronal migration disorders have been recognized from neuropathological studies for over 100 years and were traditionally thought to be associated with severe neurological impairment and to cause death at an early age. However, the advent of modern high resolution magnetic resonance imaging has resulted in the detection of NMDs in living patients. These brain lesion appear to underlie some forms of human epilepsy and are associated with mental retardation. Freezing lesions of the developing rat brain reproduce many of the anatomical findings in human cortex. Freeze-induced microgyria will be used as a model system for studying the consequences of cortical malformations . The principal aim of the proposed research is to determine the mechanisms underlying epileptiform discharges originating from experimentally induced microgyria in rat neocortex. Proposed studies will use quantitative biophysical methods, including whole-cell patch clamping of visually identified neurons and optical imaging, to identify the cellular abnormalities which underlie epileptiform discharges in focal gyral anomalies. It is planned: 1) to investigate if there is a loss of GABA-mediated inhibition in the microgyrus and adjacent region; 2) to determine if alterations in excitatory amino acid mediated excitatory synaptic transmission are present in microgyri; 3) to ascertain if metabotropic glutamate receptors are altered in microgyri, and 4) to characterize the site of origin and pattern of spread of epileptiform discharges in microgyri using voltage-sensitive dyes and optical imaging techniques. The proposed studies will increase our understanding of basic mechanisms of epileptogenesis in cortical malformations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022373-14
Application #
2714447
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Jacobs, Margaret
Project Start
1986-04-01
Project End
2000-05-31
Budget Start
1998-06-01
Budget End
1999-05-31
Support Year
14
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Physiology
Type
Schools of Dentistry
DUNS #
004514360
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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