Abstract
Global expression profiling of neurologic or psychiatric disorders has been confounded by variability among laboratories, animal models, tissues sampled, and experimental platforms, with the result being that few genes demonstrate consistent expression changes. We attempted to minimize these confounds by pooling dentate granule cell transcriptional profiles from 164 rats in seven laboratories, using three status epilepticus (SE) epilepsy models (pilocarpine, kainate, self-sustained SE), plus amygdala kindling. In each epilepsy model, RNA was harvested from laser-captured dentate granule cells from six rats at four time points early in the process of developing epilepsy, and data were collected from two independent laboratories in each rodent model except SSSE. Hierarchical clustering of differentially-expressed transcripts in the three SE models revealed complete separation between controls and SE rats isolated 1 day after SE. However, concordance of gene expression changes in the SE models was only 26–38% between laboratories, and 4.5% among models, validating the consortium approach. Transcripts with unusually highly variable control expression across laboratories provide a ‘red herring’ list for low-powered studies.
Highlights
Background and SummaryEpileptogenesis is the process that causes networks in a normal brain to become a source of epileptic seizures
Among the numerous triggers of this process is a de novo bout of convulsive status epilepticus (SE)[1], which is defined operationally as seizures lasting more than 5 min, or a cluster of seizures that occur so closely together that full consciousness is not regained between seizures[2]
We assembled a group of laboratories into an ‘epilepsy microarray consortium’ to create epileptic rats using a variety of models, with the broad objective of creating a reliable dataset of transcriptional profiles in a single neuron type during the early phase of epileptogenesis
Summary
Epileptogenesis is the process that causes networks in a normal brain to become a source of epileptic seizures. Discrepancies among studies likely reflect a combination of low statistical power and technical factors such as differences in the selection of species, variability in model methods, different brain regions selected for study, and the predominant cell type that was investigated To address these issues, we assembled a group of laboratories into an ‘epilepsy microarray consortium’ to create epileptic rats using a variety of models, with the broad objective of creating a reliable dataset of transcriptional profiles in a single neuron type during the early phase of epileptogenesis. The initial goals of this study were to: a) identify model-independent transcriptional changes in dentate granule cells that might point to novel intervention targets for epileptogenesis, b) characterize the basal transcriptional profile of dentate granule cells, and c) identify genes that have highly variable expression. The data from untreated rats were obtained from 41 animals across seven laboratories, and provide a comprehensive picture of the basal transcriptional profile of dentate granule cells
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