MicroRNA-34a upregulation during seizure-induced neuronal death. Takanori Sano J P. Reynolds Eva M. Jimenez-Mateos S Matsushima W Taki David C. Henshall 10779/rcsi.10791200.v1 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> 2019-11-22 16:58:02 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