Human focal cortical dysplasia (FCD) is a developmental brain malformation characterized histologically by disorganized cerebral cortical cytoarchitecture and lamination. FCD is associated with several mental disorders including mental retardation (MR) and autism. FCD likely results from abnormal neuronal migration during corticoneogenesis although the molecular events that culminate in aberrant cortical lamination are unknown. Previous work has suggested that FCD neurons may have failed to terminally differentiate prior to migration since these cells express proteins, such as the intermediate filament nestin, that are typically identified in immature neuronal precursor cells. These, dysplastic neurons may not express other developmentally appropriate genes necessary to complete migration and lamination. This proposal will describe three approaches to study the developmental and molecular pathogenesis of FCD. First, expression of transcription factors, neurotrophic factors/receptors and cell adhesion molecules mRNAs will be assayed in single nestin- or MAP1B-immunolabeled cells in human FCD specimens and compared with normal cortical neurons, and neuronal precursors in the ventricular zone. Because expression of these candidate genes varies during early development and because they have been implicated in corticogenesis, coordinate change in their relative abundance will provide insights into molecular pathways altered in FCD. Second, developmentally inappropriate genes such as s nestin or MAP1B will be overexpressed in cortical slice cultures and effects on migration will be assayed. Finally, dynamic changes in gene expression will be assayed in actively migrating neurons in animal models of FCD including administration of exogenous neurotrophins or antisense oligonucleotides. It is anticipated that these studies will provide for the first time a view of altered gene expression in FCD, which will shed light on the pathogenesis of these lesions. Furthermore, in identifying alterations in specific genes, the relationship between FCD and mental disorders can be rendered. These analyses may point toward new avenues for therapy.
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