10779/rcsi.10791200.v1 Takanori Sano Takanori Sano J P. Reynolds J P. Reynolds Eva M. Jimenez-Mateos Eva M. Jimenez-Mateos S Matsushima S Matsushima W Taki W Taki David C. Henshall David C. Henshall MicroRNA-34a upregulation during seizure-induced neuronal death. Royal College of Surgeons in Ireland 2019 Animals Apoptosis Argonaute Proteins Benzothiazoles Hippocampus Immunoprecipitation Kainic Acid Male Mice Inbred C57BL MicroRNAs Protein Binding Seizures Toluene Tumor Suppressor Protein p53 Up-Regulation Physiology Medical Physics 2019-11-22 16:58:02 Journal contribution https://repository.rcsi.com/articles/journal_contribution/MicroRNA-34a_upregulation_during_seizure-induced_neuronal_death_/10791200 <p>MicroRNAs (miRNAs) are short, noncoding RNAs that function as posttranscriptional regulators of gene expression by controlling translation of mRNAs. A subset of miRNAs may be critical for the control of cell death, including the p53-regulated miRNA, miR-34a. Because seizures activate p53, and p53-deficient mice are reportedly resistant to damage caused by prolonged seizures, we investigated the role of miR-34a in seizure-induced neuronal death in vivo. Status epilepticus was induced by intra-amygdala microinjection of kainic acid in mice. This led to an early (2 h) multifold upregulation of miR-34a in the CA3 and CA1 hippocampal subfields and lower protein levels of mitogen-activated kinase kinase kinase 9, a validated miR-34a target. Immunoprecipitation of the RNA-induced silencing complex component, Argonaute-2, eluted significantly higher levels of miR-34a after seizures. Injection of mice with pifithrin-α, a putative p53 inhibitor, prevented miR-34a upregulation after seizures. Intracerebroventricular injection of antagomirs targeting miR-34a reduced hippocampal miR-34a levels and had a small modulatory effect on apoptosis-associated signaling, but did not prevent hippocampal neuronal death in models of either severe or moderate severity status epilepticus. Thus, prolonged seizures cause subfield-specific, temporally restricted upregulation of miR-34a, which may be p53 dependent, but miR-34a is probably not important for seizure-induced neuronal death in this model.</p>