This application is for a Mentored Clinical Scientist Development Award (K08) for Dr. Aristea S. Galanopoulou, sponsored by Dr. Solomon L. Mosh. Dr Galanopoulou is an MD (Medical School of Athens) PhD (McGill University) trained in Neurology and Clinical Neurophysiology at Albert Einstein College of Medicine, where she is currently Assistant Professor. At McGill, Dr. Galanopoulou was trained in Molecular Biology and in vitro gene delivery methods. At Albert Einstein College of Medicine she has used in vivo experimental methods pertaining to seizure research. Dr. Galanopoulou's long- term goals are to employ novel molecular biology based approaches to develop effective treatments for epilepsy. The substantia nigra pars reticulata (SNR) has crucial role in seizure control. Intranigral infusions of muscimol, a GABAA receptor agonist, have sex, age and region specific effects on seizures. This proposal will study the role of the potassium-chloride co-transporter KCC2 in the sexual differentiation of GABAA responsive male infantile rat SNR neurons, which determine its function in seizure control. KCC2 switches hippocampal GABAA receptors from depolarizing to hyperpolarizing. Dr. Galanopoulou's findings suggest that the level of KCC2 in the SNR may determine whether GABAA receptor activation is pro-convulsant or not and correlate with sex-specific membrane responses and patterns of estradiol signaling. These data raise the possibility of accelerating the development of efficient control systems for seizures, by over expressing KCC2 and altering the sexual phenotype of male SNR. Dr. Galanopoulou will test whether in vivo over expression of KCC2 in the SNR of PN21 male rats abolishes: 1) the muscimol-induced depolarization and calcium rise, 2) the estradiol-mediated down regulation of phosphorylated CREB, 3) the muscimol-induced pro-convulsant SNR responses, and 4) will identify other genes regulated by KCC2, which suppress the testosterone-organized muscimol-sensitive proconvulsant effects of male rat SNR. This research will entail in vivo gene delivery using adeno-associated viruses, stereotactic surgery, immunochemistry, in situ hybridization, seizure induction, gramicidin perforated patch clamp, fura-2AM imaging, confocal microscopy, stereological cell counting, DNA microarrays and statistics. Albert Einstein College of Medicine will offer the necessary mentoring, laboratory space, equipment and training opportunities to achieve these goals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS045243-04
Application #
7084566
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fureman, Brandy E
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$172,800
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Chudomel, O; Hasson, H; Bojar, M et al. (2015) Age- and sex-related characteristics of tonic GABA currents in the rat substantia nigra pars reticulata. Neurochem Res 40:747-57
Pardo, Carlos A; Nabbout, Rima; Galanopoulou, Aristea S (2014) Mechanisms of epileptogenesis in pediatric epileptic syndromes: Rasmussen encephalitis, infantile spasms, and febrile infection-related epilepsy syndrome (FIRES). Neurotherapeutics 11:297-310
Ono, Tomonori; Moshé, Solomon L; Galanopoulou, Aristea S (2011) Carisbamate acutely suppresses spasms in a rat model of symptomatic infantile spasms. Epilepsia 52:1678-84
Raffo, Emmanuel; Coppola, Antonietta; Ono, Tomonori et al. (2011) A pulse rapamycin therapy for infantile spasms and associated cognitive decline. Neurobiol Dis 43:322-9
Galanopoulou, Aristea S (2010) Mutations affecting GABAergic signaling in seizures and epilepsy. Pflugers Arch 460:505-23
Chudomelova, Lenka; Scantlebury, Morris H; Raffo, Emmanuel et al. (2010) Modeling new therapies for infantile spasms. Epilepsia 51 Suppl 3:27-33
Scantlebury, Morris H; Galanopoulou, Aristea S; Chudomelova, Lenka et al. (2010) A model of symptomatic infantile spasms syndrome. Neurobiol Dis 37:604-12
Coppola, Antonietta; Moshé, Solomon L (2009) Why is the developing brain more susceptible to status epilepticus? Epilepsia 50 Suppl 12:25-6
Chudomel, O; Herman, H; Nair, K et al. (2009) Age- and gender-related differences in GABAA receptor-mediated postsynaptic currents in GABAergic neurons of the substantia nigra reticulata in the rat. Neuroscience 163:155-67
Galanopoulou, Aristea S; Moshé, Solomon L (2009) The epileptic hypothesis: developmentally related arguments based on animal models. Epilepsia 50 Suppl 7:37-42

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