This application is for a Mentored Clinical Scientist Development Award (K08). The candidate obtained clinical training in Child Neurology at UCLA, and then completed a two-year fellowship in neuropharmacology at the National Institutes of Health (Epilepsy Research Branch, NINDS) prior to taking his current faculty appointment in 1994 at the University of Washington. The long- term career goal of the candidate is to study the relationship between ion channels and epileptogenesis, to identify potentially novel treatments for developmental epilepsies that have a rational molecular basis, and to explore the relationship between genetic susceptibility and environmental influence in the pathogenesis of the developmental epilepsies. The university medical center and Children's Hospital possess complementary strengths in the basic neurosciences and clinical pediatric epileptology, respectively. Laboratory space, equipment, and specialized consultants are available to the candidate on a collaborative basis provided by several academic departments. This environment is ideally suited for supporting and fostering the candidate's long-term professional goals. We have chosen as our experimental model the mKv1.1 potassiumchannel single gene mouse mutant which exhibits spontaneous seizures early in development. First, we hypothesize that loss of a specific potassium channel subunit in the CA 3 region of the hippocampus results in a functional alteration in physiological properties of pyramidal neurons such that they became hyperexcitable and prone to excessive synchronization of discharge. Second, we postulate that pharmacological treatment can alter the natural course of the epilepsy and may protect the animal from neuronal injury as a consequence of repeated seizures. Finally, we will explore whether partial expression of the mKv1.1 gene in plus/minus mice, resulting in an enhanced susceptibility to seizures, can be modified by secondary exposure to kainic acid (a potent convulsant and neurotoxin) early in development. Initial efforts will involve electrophysiological recordings from CA3 pyramidal neurons in hippocampal slices taken from null mutants at different ages; intrinsic and synaptic properties of these cells, as well as whole-cell potassium currents, will be measured with extracellular, intracellular and patch-clamp recording techniques. Video-EEG monitoring (with depth electrodes) will be employed to document epileptiform or seizure activity in the hippocampus, and histochemical analysis of neuronal damage and/or plasticity will be made with routine and special (e.g., Timm) stains. The results of these studies may lead to an improved understanding of the role ion channels play in epileptogenesis, may shed light on the controversial issue of whether chronic seizures can cause brain damage, and will provide a framework for further studies examining genetic and environmental interactions in the developing brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS001974-06
Application #
6393137
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fureman, Brandy E
Project Start
1997-07-23
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2004-06-30
Support Year
6
Fiscal Year
2001
Total Cost
$109,620
Indirect Cost
Name
University of California Irvine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
Golumbek, P T; Rho, J M; Spain, W J et al. (2004) Effects of flunarizine on spontaneous synaptic currents in rat neocortex. Naunyn Schmiedebergs Arch Pharmacol 370:176-82
Simeone, Timothy A; Sanchez, Russell M; Rho, Jong M (2004) Molecular biology and ontogeny of glutamate receptors in the mammalian central nervous system. J Child Neurol 19:343-60; discussion 361
Sullivan, Patrick G; Rippy, Nancy A; Dorenbos, Kristina et al. (2004) The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann Neurol 55:576-80
Rho, Jong M; Sarnat, Harvey B; Sullivan, Patrick G et al. (2004) Lack of long-term histopathologic changes in brain and skeletal muscle of mice treated with a ketogenic diet. J Child Neurol 19:555-7
Simeone, Timothy A; Donevan, Sean D; Rho, Jong M (2003) Molecular biology and ontogeny of gamma-aminobutyric acid (GABA) receptors in the mammalian central nervous system. J Child Neurol 18:39-48; discussion 49
Donevan, Sean D; White, H Steve; Anderson, Gail D et al. (2003) Voltage-dependent block of N-methyl-D-aspartate receptors by the novel anticonvulsant dibenzylamine, a bioactive constituent of L-(+)-beta-hydroxybutyrate. Epilepsia 44:1274-9
Rho, Jong M; Anderson, Gail D; Donevan, Sean D et al. (2002) Acetoacetate, acetone, and dibenzylamine (a contaminant in l-(+)-beta-hydroxybutyrate) exhibit direct anticonvulsant actions in vivo. Epilepsia 43:358-61
van Brederode, J F; Rho, J M; Cerne, R et al. (2001) Evidence of altered inhibition in layer V pyramidal neurons from neocortex of Kcna1-null mice. Neuroscience 103:921-9
Szot, P; Weinshenker, D; Rho, J M et al. (2001) Norepinephrine is required for the anticonvulsant effect of the ketogenic diet. Brain Res Dev Brain Res 129:211-4
Rho, J M; Storey, T W (2001) Molecular ontogeny of major neurotransmitter receptor systems in the mammalian central nervous system: norepinephrine, dopamine, serotonin, acetylcholine, and glycine. J Child Neurol 16:271-280; discussion 281

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