MicroRNA-22 Controls Aberrant Neurogenesis and Changes in Neuronal Morphology After Status Epilepticus

Abstract

Prolonged seizures (status epilepticus, SE) may drive hippocampal dysfunction and epileptogenesis, at least partly, through an elevation in neurogenesis, dysregulation of migration and aberrant dendritic arborization of newly-formed neurons. MicroRNA-22 was recently found to protect against the development of epileptic foci, but the mechanisms remain incompletely understood. Here, we investigated the contribution of microRNA-22 to SE-induced aberrant adult neurogenesis. SE was induced by intraamygdala microinjection of kainic acid (KA) to model unilateral hippocampal neuropathology in mice. MicroRNA-22 expression was suppressed using specific oligonucleotide inhibitors (antagomir-22) and newly-formed neurons were visualized using the thymidine analog iodo-deoxyuridine (IdU) and a green fluorescent protein (GFP)-expressing retrovirus to visualize the dendritic tree and synaptic spines. Using this approach, we quantified differences in the rate of neurogenesis and migration, the structure of the apical dendritic tree and density and morphology of dendritic spines in newly-formed neurons.SE resulted in an increased rate of hippocampal neurogenesis, including within the undamaged contralateral dentate gyrus (DG). Newly-formed neurons underwent aberrant migration, both within the granule cell layer and into ectopic sites. Inhibition of microRNA-22 exacerbated these changes. The dendritic diameter and the density and average volume of dendritic spines were unaffected by SE, but these parameters were all elevated in mice in which microRNA-22 was suppressed. MicroRNA-22 inhibition also reduced the length and complexity of the dendritic tree, independently of SE. These data indicate that microRNA-22 is an important regulator of morphogenesis of newly-formed neurons in adults and plays a role in supressing aberrant neurogenesis associated with SE.

Genetic deletion of microRNA-22 blunts the inflammatory transcriptional response to status epilepticus and exacerbates epilepsy in mice

“…To the best of our knowledge, this is the rst report showing deletion of a single miRNA in a model of status epilepticus results in an altered epilepsy phenotype. The nding supports a role for miR-22 in suppressing hyper-excitability in response to an epilepsy-precipitating injury [16,26]. The accelerated and exacerbated phenotype in miR-22 -/mice matches the overall ndings from studies that used ASOs to reduce miR-22 levels in the same model [16].…”

“…While we did not observe differences in status epilepticus in the intraamygdala kainic acid model, miR-22-de cient mice may display altered vulnerability to other chemoconvulsants or epileptogenic injuries. Moreover, neuronal microstructure or subtle cellular dysorganisation may have been missed presently and recent work has shown that inhibiting miR-22 after status epilepticus produces changes to dendritic branching patterns in new hippocampal neurons [26]. Finally, a limit of the present study is that we did not perform a recovery experiment.…”

“…Since spontaneous seizures were more frequent and lasted longer in miR-22de cient mice, miR-22 may have targets that in uence ictogenesis and seizure termination, the mechanisms of which remain incompletely understood [27]. More broadly, the ndings may be clinically relevant since miR-22 is expressed within the hippocampus of patients with drug-resistant epilepsy [26].…”

Genetic deletion of microRNA-22 blunts the inflammatory transcriptional response to status epilepticus and exacerbates epilepsy in mice

“…While we did not observe differences in status epilepticus in the intraamygdala kainic acid model, miR-22-deficient mice may display altered vulnerability to other chemoconvulsants or epileptogenic injuries. Moreover, neuronal microstructure or subtle cellular dysorganisation may have been missed presently and recent work has shown that inhibiting miR-22 after status epilepticus produces changes to dendritic branching patterns in hippocampal neurons [25]. Finally, it would be interesting to determine if the knockout phenotype we observed can be recovered or obviated by the reintroduction of miR-22, for example by delivery of a mimic [16,36].…”

Identification and classification of hubs in miRNA target gene networks in human neural stem/progenitor cells following Japanese encephalitis virus infection

“…miR-9 also facilitates influenza A infection in A549 cells 36 . miR-22 is shown to control adult neurogenesis, neuronal migration and dendritic arborization 37 . It is also considered as a serum biomarker for hepatitis B infection 38 .…”