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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08MH001658-05
Application #
6625361
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Desmond, Nancy L
Project Start
1998-12-01
Project End
2004-11-30
Budget Start
2002-12-16
Budget End
2004-11-30
Support Year
5
Fiscal Year
2003
Total Cost
$168,326
Indirect Cost
Name
University of Pennsylvania
Department
Neurology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Hua, Yue; Crino, Peter B (2003) Single cell lineage analysis in human focal cortical dysplasia. Cereb Cortex 13:693-9
Maldonado, Michelle; Baybis, Marianna; Newman, David et al. (2003) Expression of ICAM-1, TNF-alpha, NF kappa B, and MAP kinase in tubers of the tuberous sclerosis complex. Neurobiol Dis 14:279-90
Ryzhova, Elena V; Crino, Peter; Shawver, Linda et al. (2002) Simian immunodeficiency virus encephalitis: analysis of envelope sequences from individual brain multinucleated giant cells and tissue samples. Virology 297:57-67
Crino, Peter B; Jin, Hong; Shumate, Melissa D et al. (2002) Increased expression of the neuronal glutamate transporter (EAAT3/EAAC1) in hippocampal and neocortical epilepsy. Epilepsia 43:211-8
Onda, Hiroaki; Crino, Peter B; Zhang, Hongbing et al. (2002) Tsc2 null murine neuroepithelial cells are a model for human tuber giant cells, and show activation of an mTOR pathway. Mol Cell Neurosci 21:561-74
Crino, Peter B; Miyata, Hajime; Vinters, Harry V (2002) Neurodevelopmental disorders as a cause of seizures: neuropathologic, genetic, and mechanistic considerations. Brain Pathol 12:212-33
Crino, Peter B (2002) Gene expression analysis as a strategy to understand the molecular pathogenesis of infantile spasms. Int Rev Neurobiol 49:367-89
White, R; Hua, Y; Scheithauer, B et al. (2001) Selective alterations in glutamate and GABA receptor subunit mRNA expression in dysplastic neurons and giant cells of cortical tubers. Ann Neurol 49:67-78

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