Co-administration of anti microRNA-124 and -137 oligonucleotides prevents hippocampal neural stem cell loss upon non-convulsive seizures

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

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Article number31
JournalFrontiers in Behavioral Neuroscience
Volume12
DOIs
Publication statusPublished - 2019

Cite this

Bielefeld, Pascal ; Schouten, Marijn ; Meijer, Guido M. ; Breuk, Marit J. ; Geijtenbeek, Karlijne ; Karayel, Sedef ; Tiaglik, Alisa ; Vuuregge, Anna H. ; Willems, Ruth A. L. ; Witkamp, Diede ; Lucassen, Paul J. ; Encinas, Juan M. ; Fitzsimons, Carlos P. / Co-administration of anti microRNA-124 and -137 oligonucleotides prevents hippocampal neural stem cell loss upon non-convulsive seizures. In: Frontiers in Behavioral Neuroscience. 2019 ; Vol. 12.
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title = "Co-administration of anti microRNA-124 and -137 oligonucleotides prevents hippocampal neural stem cell loss upon non-convulsive seizures",
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.",
author = "Pascal Bielefeld and Marijn Schouten and Meijer, {Guido M.} and Breuk, {Marit J.} and Karlijne Geijtenbeek and Sedef Karayel and Alisa Tiaglik and Vuuregge, {Anna H.} and Willems, {Ruth A. L.} and Diede Witkamp and Lucassen, {Paul J.} and Encinas, {Juan M.} and Fitzsimons, {Carlos P.}",
year = "2019",
doi = "10.3389/fnmol.2019.00031",
language = "English",
volume = "12",
journal = "Frontiers in Behavioral Neuroscience",
issn = "1662-5153",
publisher = "Frontiers Media S.A.",

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Bielefeld, P, Schouten, M, Meijer, GM, Breuk, MJ, Geijtenbeek, K, Karayel, S, Tiaglik, A, Vuuregge, AH, Willems, RAL, Witkamp, D, Lucassen, PJ, Encinas, JM & Fitzsimons, CP 2019, 'Co-administration of anti microRNA-124 and -137 oligonucleotides prevents hippocampal neural stem cell loss upon non-convulsive seizures' Frontiers in Behavioral Neuroscience, vol. 12, 31. https://doi.org/10.3389/fnmol.2019.00031

Co-administration of anti microRNA-124 and -137 oligonucleotides prevents hippocampal neural stem cell loss upon non-convulsive seizures. / Bielefeld, Pascal; Schouten, Marijn; Meijer, Guido M.; Breuk, Marit J.; Geijtenbeek, Karlijne; Karayel, Sedef; Tiaglik, Alisa; Vuuregge, Anna H.; Willems, Ruth A. L.; Witkamp, Diede; Lucassen, Paul J.; Encinas, Juan M.; Fitzsimons, Carlos P.

In: Frontiers in Behavioral Neuroscience, Vol. 12, 31, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Co-administration of anti microRNA-124 and -137 oligonucleotides prevents hippocampal neural stem cell loss upon non-convulsive seizures

AU - Bielefeld, Pascal

AU - Schouten, Marijn

AU - Meijer, Guido M.

AU - Breuk, Marit J.

AU - Geijtenbeek, Karlijne

AU - Karayel, Sedef

AU - Tiaglik, Alisa

AU - Vuuregge, Anna H.

AU - Willems, Ruth A. L.

AU - Witkamp, Diede

AU - Lucassen, Paul J.

AU - Encinas, Juan M.

AU - Fitzsimons, Carlos P.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85064208752&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/30837840

U2 - 10.3389/fnmol.2019.00031

DO - 10.3389/fnmol.2019.00031

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VL - 12

JO - Frontiers in Behavioral Neuroscience

JF - Frontiers in Behavioral Neuroscience

SN - 1662-5153

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ER -