Cortical dysplasia is thought to arise from abnormalities in brain cell proliferation, migration, and/or differentiation. Advances in biomedical technology - medical genetics and brain imaging - have confirmed that a high proportion of early-onset epilepsies is associated with such structural abnormalities. Despite this high correlation, we still do not understand what features of dysplasia lead to epilepsy - the cause and effect relationship between structural and and functional abnormalities. To gain some insight into the epileptogenic components of dysplastic brain tissue, we propose to analyze animal models in which dysplastic abnormalities are or are not associated with seizure activity. We will test two general hypotheses. First, disruption of normal cortical organization (as seen in models of heterotopia) leads to epileptigenicity by virtue of subsequent reorganization. In such cases, we propose that heterotopic cell regions are rarely the site of seizures initiation, but serves to distribute epileptic discharge generated by surrounding brain regions. To test this hypothesis, we will characterize heterotopic dysplasia seen in the methylazoxymethanol (MAM) rat and in the p35 mouse knockout models of neuronal migration disorder. Second, we hypothesize that disruption of differentiation programs as seen in syndromes such as tuberous sclerosis gives rise to cells with aberrant electrical activity. properties that can trigger epileptic discharges. In such cases we propose that the ''tuber'' containing the aberrant cells serves as an initiator zone. We will explore this hypothesis in the Eker rat model of tuberous sclerosis (heterozygous mutation of the TSC2 gene). Finally, key characteristics obtained from animal model studies will be compared to morphological and electrophysiological properties of human cortical tissue resected from patients with cortical dysplasia and medically-intractable epilepsy. By identifying the critical features that are essential for epileptic activity, we will be able to develop more effective treatments that target seizure-causing aberrations in brain structure and function.
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