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Department of Neurosurgery, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Published: September 2009
AI Article Synopsis
Article Abstract
Purpose: Cortical Dysplasia (CD) is the histopathological substrate in almost half of all drug-resistant focal epilepsies. Little is known about the gene expression profile of CD. As such information may help target therapeutics more effectively, our aim was to perform a gene expression analysis of an animal model of cortical dysplasia induced by in utero irradiation.
Methods: Nine offspring from irradiated animals, and nine age-matched controls were sacrificed at post-natal day 60. Cortical and hippocampal regions were separated, and total ribonucleic acid (RNA) was extracted using a commercially available kit (Qiagen). RNA was then subjected to a gene expression analysis using an oligonucleotide microarray platform (Illumina). After statistical analysis, genes were considered differentially expressed when a p value less than 0.001 was observed. Real-time, quantitative polymerase chain reaction (RT-qPCR) was used to confirm microarray results for three genes via the Livak method.
Results: Twenty three genes from cortical tissue met criteria for altered gene expression. Six genes from cortex seemed relevant to the pathogenesis of CD. Two genes that promoted cell survival (connective tissue growth factor and peroxiredoxin) were upregulated. One gene that promoted excitotoxic neurodegeneration (latrophilin-2) was downregulated. Two genes involved in glutamate (protein kinase C-alpha) and AMPA receptor recycling (NEEP-21) were downregulated. One gene, (Shank-1) involved in the control of dendritic maturation, was downregulated.
Conclusion: Gene expression analysis in this animal model revealed some of the potential mechanisms by which CD may lead to the phenotype of intractable epilepsy. The downregulation of genes that are involved in glutamate and AMPA receptor recycling may lead to increased excitability. Disinhibition of aberrant dendritic branching, resulting from a downregulation of Shank-1, may also result in an increase in sprouting, excitation and/or hypersynchrony. Finally, genes promoting cell survival, either directly (connective tissue growth factor, peroxiredoxin) or indirectly (latrophilin-2) may allow CD tissue to survive the excitotoxic injury that it produces, thus allowing it to perpetuate the epileptic condition over time.
