TY - JOUR
T1 - MiRNA expression profile after status epilepticus and hippocampal neuroprotection by targeting miR-132
AU - Jimenez-Mateos, Eva M.
AU - Bray, Isabella
AU - Sanz-Rodriguez, Amaya
AU - Engel, Tobias
AU - McKiernan, Ross C.
AU - Mouri, Genshin
AU - Tanaka, Katsuhiro
AU - Sano, Takanori
AU - Saugstad, Julie A.
AU - Simon, Roger P.
AU - Stallings, Raymond L.
AU - Henshall, David C.
N1 - Funding Information:
Supported by Science Foundation Ireland grant 08/IN1/B1875 (D.C.H.), Health Research Board grant PHD/2007/11 , a postdoctoral fellowship from the Irish Research Council for Science Engineering and Technology (E.J.-M.), the National Biophotonics and Imaging Platform Ireland, and the Children's Medical and Research Foundation.
PY - 2011/11
Y1 - 2011/11
N2 - When an otherwise harmful insult to the brain is preceded by a brief, noninjurious stimulus, the brain becomes tolerant, and the resulting damage is reduced. Epileptic tolerance develops when brief seizures precede an episode of prolonged seizures (status epilepticus). MicroRNAs (miRNAs) are small, noncoding RNAs that function as post-transcriptional regulators of gene expression. We investigated how prior seizure preconditioning affects the miRNA response to status epilepticus evoked by intra-amygdalar kainic acid in mice. The miRNA was extracted from the ipsilateral CA3 subfield 24 hours after focal-onset status epilepticus in animals that had previously received either seizure preconditioning (tolerance) or no preconditioning (injury), and mature miRNA levels were measured using TaqMan low-density arrays. Expression of 21 miRNAs was increased, relative to control, after status epilepticus alone, and expression of 12 miRNAs was decreased. Increased miR-132 levels were matched with increased binding to Argonaute-2, a constituent of the RNA-induced silencing complex. In tolerant animals, expression responses of >40% of the injury-group-detected miRNAs differed, being either unchanged relative to control or down-regulated, and this included miR-132. In vivo microinjection of locked nucleic acid-modified oligonucleotides (antagomirs) against miR-132 depleted hippocampal miR-132 levels and reduced seizure-induced neuronal death. Thus, our data strongly suggest that miRNAs are important regulators of seizure-induced neuronal death.
AB - When an otherwise harmful insult to the brain is preceded by a brief, noninjurious stimulus, the brain becomes tolerant, and the resulting damage is reduced. Epileptic tolerance develops when brief seizures precede an episode of prolonged seizures (status epilepticus). MicroRNAs (miRNAs) are small, noncoding RNAs that function as post-transcriptional regulators of gene expression. We investigated how prior seizure preconditioning affects the miRNA response to status epilepticus evoked by intra-amygdalar kainic acid in mice. The miRNA was extracted from the ipsilateral CA3 subfield 24 hours after focal-onset status epilepticus in animals that had previously received either seizure preconditioning (tolerance) or no preconditioning (injury), and mature miRNA levels were measured using TaqMan low-density arrays. Expression of 21 miRNAs was increased, relative to control, after status epilepticus alone, and expression of 12 miRNAs was decreased. Increased miR-132 levels were matched with increased binding to Argonaute-2, a constituent of the RNA-induced silencing complex. In tolerant animals, expression responses of >40% of the injury-group-detected miRNAs differed, being either unchanged relative to control or down-regulated, and this included miR-132. In vivo microinjection of locked nucleic acid-modified oligonucleotides (antagomirs) against miR-132 depleted hippocampal miR-132 levels and reduced seizure-induced neuronal death. Thus, our data strongly suggest that miRNAs are important regulators of seizure-induced neuronal death.
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U2 - 10.1016/j.ajpath.2011.07.036
DO - 10.1016/j.ajpath.2011.07.036
M3 - Article
C2 - 21945804
AN - SCOPUS:80054998780
SN - 0002-9440
VL - 179
SP - 2519
EP - 2532
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -