Co-administration of Anti microRNA-124 and -137 Oligonucleotides Prevents Hippocampal Neural Stem Cell Loss Upon Non-convulsive Seizures.

Pascal Bielefeld,Marijn Schouten,Ruth A.L Willems,Marit J Breuk,Sedef Karayel,Carlos P Fitzsimons,Alisa Tiaglik,Guido M Meijer,Juan M Encinas,Diede Witkamp,Karlijne Geijtenbeek,Anna H Vuuregge,Paul J Lucassen

doi:10.3389/fnmol.2019.00031

Abstract

Convulsive seizures promote adult hippocampal neurogenesis (AHN) through a transient activation of neural stem/progenitor cells (NSPCs) in the subgranular zone (SGZ) of the dentate gyrus (DG). However, in a significant population of epilepsy patients, non-convulsive seizures (ncSZ) are observed. The response of NSPCs to non-convulsive seizure induction has not been characterized before. We here studied first the short-term effects of controlled seizure induction on NSPCs fate and identity. We induced seizures of controlled intensity by intrahippocampally injecting increasing doses of the chemoconvulsant kainic acid (KA) and analyzed their effect on subdural EEG recordings, hippocampal structure, NSPC proliferation and the number and location of immature neurons shortly after seizure onset. After establishing a KA dose that elicits ncSZ, we then analyzed the effects of ncSZ on NSPC proliferation and NSC identity in the hippocampus. ncSZ specifically triggered neuroblast proliferation, but did not induce proliferation of NSPCs in the SGZ, 3 days post seizure onset. However, ncSZ induced significant changes in NSPC composition in the hippocampus, including the generation of reactive NSCs. Interestingly, intrahippocampal injection of a combination of two anti microRNA oligonucleotides targeting microRNA-124 and -137 normalized neuroblast proliferation and prevented NSC loss in the DG upon ncSZ. Our results show for the first time that ncSZ induce significant changes in neuroblast proliferation and NSC composition. Simultaneous antagonism of both microRNA-124 and -137 rescued seizure-induced alterations in NSPC, supporting their coordinated action in the regulation of NSC fate and proliferation and their potential for future seizure therapies.

Highlights

Convulsive seizures affect the hippocampus and promote adult hippocampal neurogenesis (AHN)
As seizures induced by 20 mM kainic acid (KA) lasted longer than 5 min, these seizures were classified as convulsive status epilepticus
These results show that granule cell dispersion and astrogliosis induced by intrahippocampal injection of KA in the dentate gyrus (DG) depend on the intensity, as assessed by EEG and a modified Racine scale, of the generated seizures indicating that they may represent meaningful cellular parameters to distinguish Convulsive seizures (cSZ) from non-convulsive seizures (ncSZ)

Summary

Introduction

Convulsive seizures (cSZ) affect the hippocampus and promote adult hippocampal neurogenesis (AHN). The excessive activation of hippocampal Neural Stem/Progenitor Cells (NSPCs) that occurs shortly after seizure onset triggers their aberrant proliferation and may thereby deplete the neurogenic NSPC pool and limit AHN (Encinas et al, 2011; Sierra et al, 2015), contributing to some of the cognitive deficits that often accompany epilepsy (Hattiangady and Shetty, 2008; Cho et al, 2015). The induction of cSZ by kainic acid (KA) activates quiescent, radial glia-like NSCs in the hippocampus, promotes their proliferation, alters cell-fate decisions and results in a shift from a mainly neurogenic toward a strongly astrogenic fate (Lugert et al, 2010; Sierra et al, 2015). The effects of ncSZ on hippocampal NSPC proliferation and cell-fate decisions remains poorly characterized

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Results

Conclusion