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.
Highlights
Prolonged or repeated seizures are damaging to the brain and can establish lasting states of hyperexcitability that produce recurrent spontaneous seizures [1, 2]
Functional studies in animals, mainly using antisense oligonucleotides (ASOs) termed antagomirs, demonstrated that targeting miRNAs can alter evoked and spontaneous seizures and neuropathological outcomes including neuronal loss and gliosis [11]. miR-22-3p, a conserved miRNA that is expressed throughout the body, including the brain [14, 15], was previously identified among upregulated miRNAs within the mouse hippocampus contralateral to the epileptogenic zone in the intraamygdala kainic acid model of status epilepticus [16]
Since miR-22 is expressed in both neurons and glia [16], we explored whether loss of miR-22 results in compensatory changes to other miRNAs enriched in these cell types
Summary
Prolonged or repeated seizures are damaging to the brain and can establish lasting states of hyperexcitability that produce recurrent spontaneous seizures (epilepsy) [1, 2]. Expression of various miRNAs is dysregulated in experimental models of status epilepticus and in resected brain tissue from patients with drug-resistant temporal lobe epilepsy [11,12,13]. This is predicted to exert an important influence on the gene expression landscape. Inhibiting miR-22 using intracerebroventricular injection of an ASO increased the frequency of spontaneous seizures, indicating that miR-22 has a protective role in the model [16]. Over-expression of miR-22 has been reported to protect in models of brain injury and additional targets of miR-22 have been identified [17, 18]
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