Reversibility of Neocortical Malformation

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DESCRIPTION (provided by applicant): A causal link between malformations of cerebral cortex and seizures is well established. Surgical removal of operable malformations can significantly reduce seizures in human patients, however for inoperable or diffuse cortical malformations, often refractory to pharmacological therapy, alternative therapies must be developed. New treatments may evolve from either the discovery of pharmacological agents that target dysplastic or displaced neurons, or from approaches to prevent or eliminate formed or forming malformations. We hypothesize that during development there is a sustained period of structural plasticity during which time neuronal migration can be restarted in displaced neurons. We further hypothesize that during this period early neocortical malformations can be regressed by the appropriate activation or expression of proteins that promote migration, or by elimination of cells that interfere with the migration of other cells. We propose to test this hypothesis by focusing our studies on a novel model of sub cortical band heterotopia (sbh) or double cortex syndrome. In preliminary studies we have found that malformations in this model can be prevented from forming by re-expressing doublecortin (DCX) in migrationally impaired neurons. Most importantly, we observe that malformation regression can occur after a malformation begins to form in early development. Understanding the developmental limits and mechanisms of heterotopia regression in this animal model is an important step to determining whether epileptogenic neuronal malformations in humans may be reversed by reactivating normal neuronal migration. PUBLIC HEALTH RELEVANCE: Seizure disorders caused by developmental malformation of the cerebral cortex are one of the most challenging forms of epilepsy to manage. Such malformations are often formed by early deficits in migration of neurons during early brain maturation. If neurons stalled in there migration during early development can be re-started, then this opens up the possibility of regressing or reversing malformations even after they have begun to form. Experiments proposed here will use a novel pre-clinical model to establish the developmental limits of restoring normal migration and of reversing formation of potentially epileptogenic malformations.