So far, the dynamic transcriptional signatures at distinct pathogenic stages early after SE in the CA region have not been examined. Here, we aimed to elucidate the transcriptional cascades triggered shortly after SE and the key transcription factors (TFs) mediating these changes. Hereby, CA1 is of particular importance as it constitutes the output point of the hippocampal tri-synaptic circuit. Only a few days after SE, the hippocampal CA1 subfield acquires the properties of an epileptogenic focus 10.Ĭurrently, it is believed that SE as a transient insult induces a specific transcriptional program that differs between distinct hippocampal subregions. CA1 represents a key anatomo-functional compartment of the tri-synaptic pathway under epileptogenic conditions 9. In experimental TLE models, including those triggered by kainic acid and pilocarpine-induced status epilepticus (SE), the hippocampal CA1 region appears to be an important site of epileptogenesis 6, 7, 8. Recent data suggest that SE induces highly variable gene expression in different cell types and compartments of the hippocampus 3, 4, 5. Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy, which is often pharmacoresistant to antiseizure medication. It involves the transition of a stable brain network into a functionally altered structure that leads to the development of spontaneously recurring seizures 2. Similar content being viewed by othersĮpileptogenesis is the process by which changes occur in the brain after a precipitating injury or insult that leads to the development of epilepsy 1. Transcription factors mediating this transcriptomic switch represent targets for new highly selected, cell type and time window-specific anti-epileptogenic strategies. CA1 quickly responds to SE by inducing transcription of genes linked to inflammation and excitation stress. Binding sites for the transcription factors Nfkb1, Spi1, Irf8, and two Runx family members, were enriched within promoters of differentially expressed genes related to major inflammatory processes, whereas the transcriptional repressors Suz12, Nfe2l2 and Rest were associated with hyperexcitability and GABA / glutamate receptor activity. Major differentially expressed mRNAs encoded primarily immediate early and excitability-related gene products, as well as genes encoding immune signalling factors. Robust transcriptomic changes were detected at 6 h after SE and at subsequent time points during early epileptogenesis. Bioinformatics was used to decipher altered gene expression, signalling cascades and their corresponding cell type profiles. RNA sequencing of CA1 was performed in the mouse pilocarpine-induced SE model at multiple time points ranging from 6 to 72 h after the initial insult. Here, we aimed to elucidate the early SE-elicited mRNA signature changes and the respective upstream regulatory cascades in CA1. The transcriptional profiles of the distinct hippocampal neurons are highly dynamic during epileptogenesis. A key role in epileptogenesis has been attributed to the CA1 region as the last relay station in the hippocampal circuit and as site of aberrant plasticity, e.g. As a consequence, the entire tri-synaptic circuit of the hippocampus is fundamentally impaired. Transient brain insults including status epilepticus (SE) can initiate a process termed ‘epileptogenesis’ that results in chronic temporal lobe epilepsy.
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