Epilepsy is a common neurological condition that effects over 1% of the adult population and greater than 2% of children. Despite numerous advances in our understanding of the basic mechanisms underlying epileptiform discharges, little is known about the molecular events that initiate enduring plasticity changes in epilepsy. Recent advances have demonstrated that long-term plasticity changes seen in the induction of epilepsy in experimental models can be caused by N-methyl-D-aspartate (NMDA) receptor activation and in many cases, have been shown to be calcium dependent. One plausible mechanism to explain the maintenance of these NMDA/Ca2+-dependent changes in neuronal excitability observed in epilepsy would be the alteration of neuronal genetic expression, causing long-lasting changes in neuronal excitability. Studies from this laboratory have demonstrated that NMDA receptor activation can produce long-term changes in gene expression of hippocampal neurons in a NMDA/Ca2+-dependent manner. Furthermore, we have shown that changes in the expression of specific gene products correlate in time with the induction of epileptogenesis in the kindling and hippocampal slice preparations and with long-term excitability changes in neurons in culture. Studies proposed in this research effort will critically test the HYPOTHESIS that long-term NMDA/Ca+-dependent changes of gene expression in hippocampal neurons underlie many of the persistent changes in neuronal excitability and result in the development of neuronal hyperexcitability and epileptiform discharge. Since epilepsy is a complex condition and no one animal model is ideally suited to study this problem, we will utilize three experimental systems at the cell, cell circuit, and whole animal model levels: 1) hippocampal neurons in culture, 2) the in vitro hippocampal slice preparation with intact neuronal circuits, and 3) an in vivo kindling model of epilepsy.
The SPECIFIC AIMS of this project are directed at testing the role of the modulation of genetic expression with the development of altered neuronal excitability in these three preparations. This project will coordinate molecular genetic, biochemical, and electrophysiological approaches to test this hypothesis by determining whether or not NMDA/Ca2+ regulated, long lasting changes in gene expression underlie alterations in neuronal excitability in these three experimental systems or are associated with epiphenomenon. These studies ultimately aim to evaluate the causality between specific changes in gene expression with epileptogenesis. Our recent data indicate that selective changes in NMDA receptor isoform expression under conditions that induce epileptic changes and hyperexcitability in these three model systems are also associated with changes in NMDA channel properties that lead to hyperexcitability in hippocampal neurons. These findings may offer direct evidence for a role of changes in NMDA channel isoform expression in producing alterations in neuronal excitability that occur during epileptogenesis in these model systems. The results from this study may provide a molecular insight into an endogenous genetic mechanism modulating some of the long lasting effects of NDMA receptor activation on neuronal excitability and may increase our understanding of the complex mechanisms that underlie the pathogenesis of epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023350-15
Application #
2858110
Study Section
Neurology A Study Section (NEUA)
Program Officer
Jacobs, Margaret
Project Start
1985-07-01
Project End
2000-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
15
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Deshpande, Laxmikant S; Sombati, Sompong; Blair, Robert E et al. (2007) Cannabinoid CB1 receptor antagonists cause status epilepticus-like activity in the hippocampal neuronal culture model of acquired epilepsy. Neurosci Lett 411:11-6
Deshpande, Laxmikant S; Blair, Robert E; Nagarkatti, Nisha et al. (2007) Development of pharmacoresistance to benzodiazepines but not cannabinoids in the hippocampal neuronal culture model of status epilepticus. Exp Neurol 204:705-13
Falenski, K W; Blair, R E; Sim-Selley, L J et al. (2007) Status epilepticus causes a long-lasting redistribution of hippocampal cannabinoid type 1 receptor expression and function in the rat pilocarpine model of acquired epilepsy. Neuroscience 146:1232-44
Deshpande, Laxmikant S; Blair, Robert E; Ziobro, Julie M et al. (2007) Endocannabinoids block status epilepticus in cultured hippocampal neurons. Eur J Pharmacol 558:52-9
Carter, Dawn S; Haider, S Naqeeb; Blair, Robert E et al. (2006) Altered calcium/calmodulin kinase II activity changes calcium homeostasis that underlies epileptiform activity in hippocampal neurons in culture. J Pharmacol Exp Ther 319:1021-31
Blair, Robert E; Deshpande, Laxmikant S; Sombati, Sompong et al. (2006) Activation of the cannabinoid type-1 receptor mediates the anticonvulsant properties of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy and status epilepticus. J Pharmacol Exp Ther 317:1072-8
DeLorenzo, Robert J; Sun, David A; Deshpande, Laxmikant S (2006) Erratum to ""Cellular mechanisms underlying acquired epilepsy: the calcium hypothesis of the induction and maintenance of epilepsy."" [Pharmacol. Ther. 105(3) (2005) 229-266] Pharmacol Ther 111:288-325
DeLorenzo, Robert J (2006) Epidemiology and clinical presentation of status epilepticus. Adv Neurol 97:199-215
Delorenzo, Robert J; Sun, David A; Deshpande, Laxmikant S (2005) Cellular mechanisms underlying acquired epilepsy: the calcium hypothesis of the induction and maintainance of epilepsy. Pharmacol Ther 105:229-66
Raza, Mohsin; Shaheen, Farzana; Choudhary, M I et al. (2004) Inhibition of sustained repetitive firing in cultured hippocampal neurons by an aqueous fraction isolated from Delphinium denudatum. J Ethnopharmacol 90:367-74

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