Neuropharmacology of A Gentic Model of Epilepsy

Heller, Allen

Abstract

The tottering mutant mouse (tg, autosomal recessive) is a presumed single-locus mutant with inherited epilepsy manifest by spontaneous focal motor seizures and frequent """"""""absence"""""""" seizures. Tottering absence seizures are correlated with stereotyped EEG events and characterized by a sensitivity to a defined class of clinical antiepileptic drugs and to pharmacological manipulation of GABA inhibition. Although the mechanism of tottering seizures is unknown, others have demonstrated an abnormal increased density of locus ceruleus noradrenergic terminals. Our studies during the past year suggest that noradrenergic activity is increased in tottering mice and that tottering absence seizures can be altered by pharmacological manipulation of noradrenergic activity. Objectives for the next year of support focus on the following questions: (1) What is the full extent and localization of the alteration of the noradrenergic activity in the tottering mutant? (2) Is there any detectable alteration in the function of other putative neurotransmitter systems with a suspected role in epileptogenesis (i.e., GABA, glycine, enkephlins)? (3) What is the relationship between observed alterations in neurotransmitter function and the epileptic phenotype? Specifically, during the next budget year we plan to investigate the distribution, density and affinity of alpha-1, alpha-2, and beta central noradrenergic receptors in tottering homozygotes using autoradiographic receptor methods. Ongoing autoradiographic studies to map the distribution of benzodiazepine, GABA, glycine, and opiate receptors in tottering homozygotes will be completed. Immunocytochemical studies to characterize GABAergic neurons will be carried out. Finally, we plan to continue comparative studies of the epileptic phenotype using the allelic mutants rolling mouse Nagoya, (tg-roI) and leaner, (tg1a). The latter studies may help to clarify the relationship between observed biochemical abnormalities and epileptogenesis and to identify and elucidate the role of modifying genes in the expression of spontaneous epilepsy).