Genetic deletion of microRNA-22 blunts the inflammatory transcriptional response to status epilepticus and exacerbates e
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RESEARCH
Open Access
Genetic deletion of microRNA-22 blunts the inflammatory transcriptional response to status epilepticus and exacerbates epilepsy in mice Luiz F. Almeida Silva1, Cristina R. Reschke1,2, Ngoc T. Nguyen1,2, Elena Langa1,2, Amaya Sanz-Rodriguez1,2, Rogerio R. Gerbatin1,2, Fernanda R. Temp1,3, Mayara L. de Freitas1,3, Ronan M. Conroy4, Gary P. Brennan1,2,5, Tobias Engel1,2 and David C. Henshall1,2*
Abstract MicroRNAs perform important roles in the post-transcriptional regulation of gene expression. Sequencing as well as functional studies using antisense oligonucleotides indicate important roles for microRNAs during the development of epilepsy through targeting transcripts involved in neuronal structure, gliosis and inflammation. MicroRNA-22 (miR-22) has been reported to protect against the development of epileptogenic brain networks through suppression of neuroinflammatory signalling. Here, we used mice with a genetic deletion of miR-22 to extend these insights. Mice lacking miR-22 displayed normal behaviour and brain structure and developed similar status epilepticus after intraamygdala kainic acid compared to wildtype animals. Continuous EEG monitoring after status epilepticus revealed, however, an accelerated and exacerbated epilepsy phenotype whereby spontaneous seizures began sooner, occurred more frequently and were of longer duration in miR-22-deficient mice. RNA sequencing analysis of the hippocampus during the period of epileptogenesis revealed a specific suppression of inflammatory signalling in the hippocampus of miR-22-deficient mice. Taken together, these findings indicate a role for miR-22 in establishing early inflammatory responses to status epilepticus. Inflammatory signalling may serve anti-epileptogenic functions and cautions the timing of anti-inflammatory interventions for the treatment of status epilepticus. Keywords: Antagomirs, kainic acid, Hippocampus, microRNA, Oligonucleotide, Temporal lobe epilepsy
Introduction Prolonged or repeated seizures are damaging to the brain and can establish lasting states of hyperexcitability that produce recurrent spontaneous seizures (epilepsy) [1, 2]. Gene expression programmes drive many of the changes underlying network reorganisation in epileptogenesis, * Correspondence: [email protected] 1 Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin D02 YN77, Ireland 2 FutureNeuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland Full list of author information is available at the end of the article
including neurodegeneration, astrogliosis, microgliosis, aberrant neurogenesis and restructured local and distant neuronal contacts, among other changes [3–5]. A number of post-transcriptional mechanisms fine-tune the gene expression landscape. Small noncoding RNAs called microRNAs (miRNA) negatively regulate gene expression by sequence-specific targeting of protein-coding transcripts [6]. Binding of a miRNA to a complementary sequence in a target mRNA is media
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