The research and career development plans proposed in this application will expand the applicant s expertise into neuropharmacology and integrative neuroscience as applied to studies of neuroplasticity and neuroprotection in animal models of neuropsychiatric disorders. The studies proposed will take advantage of the recent observation that exposure to brief, highly controlled seizures induced by low-intensity eLeciroconvulsive shock (ECS), confer a marked resistance to neuronal cell death induced by diverse insults This effect is accompanied by a marked induction of expression of specific neurotrophic factors in lhnbic system regions. The working hypothesis for the proposed studies is that enhanced receptor-mediated actions of the neurotrophic factors are a crucial component of the neuroprotective influence of ECS exposure. In particular, the extent to which receptors for two major neurotrophic factors, basic fibroblast growth factor (bFGF) and nerve growth factor (NGF), become activated and/or upregulated following repeated ECS treatment will be evaluated in specific brain areas of rats.
The Specific Aims will test whether I) repeated ECS results in activation and/or enhanced biosynthesis of receptors for bFGF and NGF in limbic system regions; 2) the neuroprotective action of repeated ECS is dependent upon activation of receptors for bFGF and/or NGF; 3) differential changes in expression of glutamate receptors will accompany the changes in bFGF and/or 4GF expression following repeated ECS; and 4) differential changes in expression of glutamate receptors are dependent upon activation of receptors for bFGF and/or NGF following repeated ECS. The experiments designed to pursue these Specific Aims will provide an ideal opportunity for the applicant to gain both theoretical and practical expertise in the combined use of pharmacological, physiological and neurohistological approaches to the study of animal models. The applicant's strong background in molecular approaches in vitro will be brought to bear on an analysis of changes occurring in vivo in the intact animal. The career development plan will facilitate a substantial shift in the applicant's research capabilities and focus, so that it will become possible for the applicant to build an independent research program devoted to elucidating molecular mechanisms that determine vulnerability to neuronal cell death in the brain of the intact animal. The ability to evaluate the multifactorial impact of therapeutic interventions in intact animal models will prepare the applicant to pursue research on animal models of neuropsychiatric disorders and place his molecular skills in the context of neurohistopathogy, pharmacology, anatomy and physiology. Structured mentored activities and short courses will guide the development of expertise in these areas necessary for the proposed studies and for the long-term career advancement of the applicant as a versatile neuroscientist.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01MH002040-02
Application #
6499221
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Desmond, Nancy L
Project Start
2001-02-15
Project End
2006-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
2
Fiscal Year
2002
Total Cost
$161,136
Indirect Cost
Name
Georgetown University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Crowe, Samantha L; Tsukerman, Susanna; Gale, Karen et al. (2011) Phosphorylation of histone H2A.X as an early marker of neuronal endangerment following seizures in the adult rat brain. J Neurosci 31:7648-56
Forcelli, Patrick A; Kim, Jinsook; Kondratyev, Alexei et al. (2011) Pattern of antiepileptic drug-induced cell death in limbic regions of the neonatal rat brain. Epilepsia 52:e207-11
Kim, Jinsook; Gale, Karen; Kondratyev, Alexei (2010) Effects of repeated minimal electroshock seizures on NGF, BDNF and FGF-2 protein in the rat brain during postnatal development. Int J Dev Neurosci 28:227-32
Conti, Giuseppe; Gale, Karen; Kondratyev, Alexei (2009) Immunohistochemical evaluation of the protein expression of nerve growth factor and its TrkA receptor in rat limbic regions following electroshock seizures. Neurosci Res 65:201-9
Kim, Jinsook; Kondratyev, Alexei; Gale, Karen (2007) Antiepileptic drug-induced neuronal cell death in the immature brain: effects of carbamazepine, topiramate, and levetiracetam as monotherapy versus polytherapy. J Pharmacol Exp Ther 323:165-73
Kim, Jin-Sook; Kondratyev, Alexei; Tomita, York et al. (2007) Neurodevelopmental impact of antiepileptic drugs and seizures in the immature brain. Epilepsia 48 Suppl 5:19-26
Katz, Irina; Kim, Jinsook; Gale, Karen et al. (2007) Effects of lamotrigine alone and in combination with MK-801, phenobarbital, or phenytoin on cell death in the neonatal rat brain. J Pharmacol Exp Ther 322:494-500
Crowe, Samantha L; Movsesyan, Vilen A; Jorgensen, Timothy J et al. (2006) Rapid phosphorylation of histone H2A.X following ionotropic glutamate receptor activation. Eur J Neurosci 23:2351-61
Fornai, Francesco; Busceti, Carla L; Kondratyev, Alexei et al. (2005) AMPA receptor desensitization as a determinant of vulnerability to focally evoked status epilepticus. Eur J Neurosci 21:455-63
Kondratyev, Alexei; Gale, Karen (2004) Latency to onset of status epilepticus determines molecular mechanisms of seizure-induced cell death. Brain Res Mol Brain Res 121:86-94

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