Cortical dysplasia is thought to arise from abnormalities in brain cell proliferation, migration, and/or differentiation. Advances in biomedical technology - medical genetics and brain imaging - have confirmed that a high proportion of early-onset epilepsies is associated with such structural abnormalities. Despite this high correlation, we still do not understand what features of dysplasia lead to epilepsy - the cause and effect relationship between structural and and functional abnormalities. To gain some insight into the epileptogenic components of dysplastic brain tissue, we propose to analyze animal models in which dysplastic abnormalities are or are not associated with seizure activity. We will test two general hypotheses. First, disruption of normal cortical organization (as seen in models of heterotopia) leads to epileptigenicity by virtue of subsequent reorganization. In such cases, we propose that heterotopic cell regions are rarely the site of seizures initiation, but serves to distribute epileptic discharge generated by surrounding brain regions. To test this hypothesis, we will characterize heterotopic dysplasia seen in the methylazoxymethanol (MAM) rat and in the p35 mouse knockout models of neuronal migration disorder. Second, we hypothesize that disruption of differentiation programs as seen in syndromes such as tuberous sclerosis gives rise to cells with aberrant electrical activity. properties that can trigger epileptic discharges. In such cases we propose that the ''tuber'' containing the aberrant cells serves as an initiator zone. We will explore this hypothesis in the Eker rat model of tuberous sclerosis (heterozygous mutation of the TSC2 gene). Finally, key characteristics obtained from animal model studies will be compared to morphological and electrophysiological properties of human cortical tissue resected from patients with cortical dysplasia and medically-intractable epilepsy. By identifying the critical features that are essential for epileptic activity, we will be able to develop more effective treatments that target seizure-causing aberrations in brain structure and function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS018895-21S1
Application #
6789182
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fureman, Brandy E
Project Start
1983-01-01
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
21
Fiscal Year
2003
Total Cost
$25,003
Indirect Cost
Name
University of California Davis
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Kinoshita, Yoshito; Wenzel, H Jurgen; Kinoshita, Chizuru et al. (2012) Acute, but reversible, kainic acid-induced DNA damage in hippocampal CA1 pyramidal cells of p53-deficient mice. Epilepsia 53 Suppl 1:125-33
Knight, Leena S; Wenzel, H Jurgen; Schwartzkroin, Philip A (2012) Inhibition and interneuron distribution in the dentate gyrus of p35 knockout mice. Epilepsia 53 Suppl 1:161-70
Wenzel, H Jurgen; Tamse, Catherine T; Schwartzkroin, Philip A (2007) Dentate development in organotypic hippocampal slice cultures from p35 knockout mice. Dev Neurosci 29:99-112
Tschuluun, Naranzogt; Wenzel, H Jurgen; Schwartzkroin, Philip A (2007) Irradiation exacerbates cortical cytopathology in the Eker rat model of tuberous sclerosis complex, but does not induce hyperexcitability. Epilepsy Res 73:53-64
Tschuluun, N; Wenzel, J H; Katleba, K et al. (2005) Initiation and spread of epileptiform discharges in the methylazoxymethanol acetate rat model of cortical dysplasia: functional and structural connectivity between CA1 heterotopia and hippocampus/neocortex. Neuroscience 133:327-42
Wenzel, H Jurgen; Patel, Leena S; Robbins, Carol A et al. (2004) Morphology of cerebral lesions in the Eker rat model of tuberous sclerosis. Acta Neuropathol (Berl) 108:97-108
Patel, Leena S; Wenzel, H Jurgen; Schwartzkroin, Philip A (2004) Physiological and morphological characterization of dentate granule cells in the p35 knock-out mouse hippocampus: evidence for an epileptic circuit. J Neurosci 24:9005-14
Lopantsev, V; Wenzel, H J; Cole, T B et al. (2003) Lack of vesicular zinc in mossy fibers does not affect synaptic excitability of CA3 pyramidal cells in zinc transporter 3 knockout mice. Neuroscience 116:237-48
Lopantsev, Valeri; Tempel, Bruce L; Schwartzkroin, Philip A (2003) Hyperexcitability of CA3 pyramidal cells in mice lacking the potassium channel subunit Kv1.1. Epilepsia 44:1506-12
Szot, P; White, S S; McCarthy, E B et al. (2001) Behavioral and metabolic features of repetitive seizures in immature and mature rats. Epilepsy Res 46:191-203

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