The proposed research aims to validate a developmental model of epileptogenesis, and delineate surrogate markers for the epileptogenic process and for associated neuronal dysfunction. A major goal of Epilepsy Research, considered an Epilepsy Benchmark, is to intervene in the epileptogenic process and abort the development of epilepsy and of related cognitive dysfunction. This goal requires: (1) validating models leading to epilepsy (spontaneous recurrent seizures) and (2) having reliable criteria or """"""""markers"""""""" for progressive epileptogenesis. The applicants have focused on the epileptogenic process culminating in temporal lobe epilepsy (TLE), and specifically on the potential causative role of prolonged febrile seizures (FS). An immature rodent model of prolonged FS has been characterized and has led to the discovery of molecular changes that promote hyperexcitability in the limbic circuit. Recent findings, using nocturnal video-EEG monitoring, indicate that a subset of adult animals that had experienced experimental prolonged FS early in life develop classical limbic seizures, with behavioral and EEG correlates. Therefore, the proposed research will test the hypotheses that the prolonged FS model can be used to predict TLE and hippocampal cognitive deficits, and that MRI lesions will serve as surrogate markers for epileptogenesis and/or hippocampal cognitive deficits. The project aims to (1) Determine the nature, distribution and time-course of abnormal MRI signals, (2) determine the value of MRI in predicting epileptogenesis, (3) determine the value of MRI in predicting the development of hippocampal neuronal dysfunction at the single cell and system levels. Based on exciting preliminary data, it is strongly believed that the outcome of this work will provide important data for future interventional strategies targeting mechanisms of disease processes - a major goal for this RFA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS049618-02
Application #
6931581
Study Section
Special Emphasis Panel (ZNS1-SRB-W (07))
Program Officer
Stables, Jim
Project Start
2004-08-02
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2007-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$151,932
Indirect Cost
Name
University of California Irvine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Choy, ManKin; Dubé, Céline M; Ehrengruber, Markus et al. (2014) Inflammatory processes, febrile seizures, and subsequent epileptogenesis. Epilepsy Curr 14:15-22
Dubé, Céline M; Ravizza, Teresa; Hamamura, Mark et al. (2010) Epileptogenesis provoked by prolonged experimental febrile seizures: mechanisms and biomarkers. J Neurosci 30:7484-94
Dubé, Céline M; Zhou, Jun-Li; Hamamura, Mark et al. (2009) Cognitive dysfunction after experimental febrile seizures. Exp Neurol 215:167-77
Dubé, Céline M; Brewster, Amy L; Baram, Tallie Z (2009) Febrile seizures: mechanisms and relationship to epilepsy. Brain Dev 31:366-71
Dube, Celine M; Brewster, Amy L; Richichi, Cristina et al. (2007) Fever, febrile seizures and epilepsy. Trends Neurosci 30:490-6
Bender, Roland A; Baram, Tallie Z (2007) Epileptogenesis in the developing brain: what can we learn from animal models? Epilepsia 48 Suppl 5:2-6
Dube, Celine; Richichi, Cristina; Bender, Roland A et al. (2006) Temporal lobe epilepsy after experimental prolonged febrile seizures: prospective analysis. Brain 129:911-22