Temporal lobe epilepsy is the most common drug-resistant form of epilepsy in adults. The reorganization of neural networks and the gene expression landscape underlying pathophysiologic network behavior in brain structures such as the hippocampus has been suggested to be controlled, in part, by microRNAs. To systematically assess their significance, we sequenced Argonaute-loaded microRNAs to define functionally engaged microRNAs in the hippocampus of three different animal models in two species and at six time points between the initial precipitating insult through to the establishment of chronic epilepsy. We then selected commonly up-regulated microRNAs for a functional in vivo therapeutic screen using oligonucleotide inhibitors. Argonaute sequencing generated 1.44 billion small RNA reads of which up to 82% were microRNAs, with over 400 unique microRNAs detected per model. Approximately half of the detected microRNAs were dysregulated in each epilepsy model. We prioritized commonly up-regulated microRNAs that were fully conserved in humans and designed custom antisense oligonucleotides for these candidate targets. Antiseizure phenotypes were observed upon knockdown of miR-10a-5p, miR-21a-5p, and miR-142a-5p and electrophysiological analyses indicated broad safety of this approach. Combined inhibition of these three microRNAs reduced spontaneous seizures in epileptic mice. Proteomic data, RNA sequencing, and pathway analysis on predicted and validated targets of these microRNAs implicated derepressed TGF-β signaling as a shared seizure-modifying mechanism. Correspondingly, inhibition of TGF-β signaling occluded the antiseizure effects of the antagomirs. Together, these results identify shared, dysregulated, and functionally active microRNAs during the pathogenesis of epilepsy which represent therapeutic antiseizure targets.
Many insignificant events in our daily life are forgotten quickly but can be remembered for longer when other memorymodulating events occur before or after them. This phenomenon has been investigated in animal models in a protocol in which weak memories persist longer if exploration in a novel context is introduced around the time of memory encoding. This study aims to understand whether other types of rewarding or novel tasks, such as rewarded learning in a T-maze and novel object recognition, can also be effective memory-modulating events. Rats were trained in a delayed matching-to-place task to encode and retrieve food locations in an event arena. Weak encoding with only one food pellet at the sample location induced memory encoding but forgetting over 24 h. When this same weak encoding was followed by a rewarded task in a T-maze, the memory persisted for 24 h. Moreover, the same persistence of memory over 24 h could be achieved by exploration in a novel box or by a rewarded T-maze task after a "non-rewarded" weak encoding. When the one-pellet weak encoding was followed by novel object exploration, the memory did not persist at 24 h. Together, the results confirm that place encoding is possible without explicit reward, and that rewarded learning in a separate task lacking novelty can be an effective memory-modulating event. The behavioral and neurobiological implications are discussed.
In order to assess mechanisms underlying inflammatory activation during extracorporeal circulation (ECC), several small animal models of ECC have been proposed recently. The majority of them are based on home-made, nonstandardized, and hardly reproducible oxygenators. The present study has generated fundamental information on the role of oxygenator of ECC in activating inflammatory signaling pathways on leukocytes, leading to systemic inflammatory response, and organ dysfunction. The present results suggest that experimental animal models of ECC used in translational research on inflammatory response should be based on standardized, reproducible oxygenators with clinical characteristics.
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