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Front Mol Neurosci. 2018 Dec 11;11:442. doi: 10.3389/fnmol.2018.00442. eCollection 2018.

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

Author information

1
Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
2
Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
3
Department of Molecular Biology, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Centro Investigación Biomédica en Red Enfermedades Neurodegenerativa (CIBERNED), Madrid, Spain.
4
FutureNeuro Research Centre, RCSI, Dublin, Ireland.
5
Department of Pharmacology and Toxicology, Veterinary Faculty, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, Madrid, Spain.
6
Data Science Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.
7
Beaumont Hospital, Dublin, Ireland.
8
Department of Biochemistry and Molecular Biology, Veterinary Faculty, Universidad Complutense de Madrid, Madrid, Spain.

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.

KEYWORDS:

epilepsy; microRNA-22; mouse model; neurogenesis; status epilepticus

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