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.
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