Malformations of the cerebral cortex are present in over 1 percent of the general human population and at least 20 - 40 percent of intractable epileptics. Increasing evidence implicates misplaced cortical neurons (cortical heterotopia) in the etiology of many of the early-onset epilepsies and some forms of mental retardation. The lack of appropriate animal models for studying the natural development of human-like heterotopia associated with epilepsy represents a major impediment to understanding: 1) the roles of cortical heterotopia in epilepsy, and 2) the developmental mechanisms responsible for generating cortical heterotopia. During the initial period of support for this project, we identified and have begun to characterize a novel mutant rat (tish) that exhibits human-like cortical heterotopia. Interestingly, some tish rats display spontaneous recurrent seizures that persist over a considerable part of their life span. The tish rat thus represents a unique animal for investigating the structural, functional, and developmental aspects of a seizure prone brain with band heterotopia. The present application will focus on disturbances in cortical inhibitory systems in the tish rat with the goal of identifying mechanisms that predispose, trigger and/or maintain seizures in a brain with band heterotopia. Preliminary results indicate that fundamental disturbances in the structure and function of GABAergic systems are present in tish rats. These modifications are in a position to predispose the tish cortex to seizure activity. Other preliminary findings indicate that errors in cellular proliferation and migration play key roles in the development of band heterotopia, and these events could selectively disturb specific populations of interneurons. The studies proposed here will expand our effors to understand mechanisms of epilepsy and developmnet in a cortex with band heterotopia. The following specific aims will be addressed: 1) Identify disturbances in GABAergic interneurons in a brain with band heterotopia and define the effects of spontaineous recurrent seizures on these interneurons, 2) Elucidate developmental events contributing to the misplacement of interneurons in band heterotopia, by comparing the roles of misplaced cellular proliferation and disordered neuronal migration, and 3) Characterize inhibitory function in identified classes of projection neruons located at heterotopic versus normotopic positions in the tish cortex, and define the effects of spontaneous recurrent seizures on the functionnal properties of neurons. The proposed studies will provide fundamental insights into the structure, function and development of a seizure-prone brain with band heterotopia.
