title: MicroRNA-34a upregulation during seizure-induced neuronal death.
abstract: 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.
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: T
authors.initials: T
authors.lastname: Sano
authors.forename: J P
authors.initials: JP
authors.lastname: Reynolds
authors.forename: E M
authors.initials: EM
authors.lastname: Jimenez-Mateos
authors.forename: S
authors.initials: S
authors.lastname: Matsushima
authors.forename: W
authors.initials: W
authors.lastname: Taki
authors.forename: D C
authors.initials: DC
authors.lastname: Henshall
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D060565:Argonaute Proteins / Q000378:metabolism; D052160:Benzothiazoles / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D047468:Immunoprecipitation; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding; D012640:Seizures / Q000378:metabolism* / Q000473:pathology; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; D052160:Benzothiazoles; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin; D007608:Kainic Acid