The proposed research project represents an effort to establish a mechanistic understanding of the development of a genetically determined pathophysiological condition underlying the seizure-prone condition of one model of epilepsy, the genetically epilepsy-prone rat (GEPR). Knowledge gained may provide insights into the pathophysiology of genetically determined epilepsy in humans. The GEPR exhibits a broadly based seizure predisposition, including heightened sensitivity to electrically and chemically induced seizures in addition to its phenotypic audiogenic seizure (AGS) susceptibility. The PI has gathered data that support the existence of two independent seizure traits in the GEPR. Developmental deficits in peripheral hearing result in a hypersensitive central auditory pathway which functions as a seizure focus for AGS ONLY. Developmental deficits in noradrenergic function constitute a general seizure propagation mechanism that is necessary for expression of ANY of the seizure prone conditions of the GEPR. Thus, the hearing deficits and noradrenergic deficits are required for AGS in the GEPR. The noradrenergic deficits (seizure propagation mechanism) and heightened seizure sensitivity have been demonstrated to developmentally precede the onset of AGS. Thus the seizure propagation mechanism appears to function independently of AGS focus. It is the seizure propagation mechanism that makes the GEPR a relevant model epilepsy, not AGS susceptibility. The present proposal will demonstrate the necessity of both developmental impairment of hearing and noradrenergic function for the induction of AGS in Sprague-Dawley rats, the rat from which the GEPR was derived. However, the bulk of the proposal will deal with the ontogeny of the noradrenergic seizure propagation mechanism developmentally at ages preceding AGS. The ontogeny of heightened electroshock sensitivity will be determined to establish the ontogeny of a functional seizure propagation mechanism. The ontogenetic nature of the noradrenergic defect will be determined by 5 complimentary biochemical and immunocytochemical studies characterizing the development of the noradrenergic pathophysiological condition in the GEPR. These studies will include: regional content of norepinephrine (NE), NE uptake, dopamine B-hydroxylase activity, noradrenergic cell counts in the locus coeruleus and noradrenergic arborization.
| Reigel, C E; Faingold, C L (1993) Innately hearing impaired Sprague-Dawley rats exhibit audiogenic seizure susceptibility following monoamine depletion. Proc West Pharmacol Soc 36:267-71 |
