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New Research, Disorders of the Nervous System

Post-injury inhibition of miR-181a promotes restoration of hippocampal CA1 neurons after transient forebrain ischemia in rats

Brian B. Griffiths, Yi-Bing Ouyang, Lijun Xu, Xiaoyun Sun, Rona G. Giffard and Creed M. Stary
eNeuro 19 August 2019, ENEURO.0002-19.2019; DOI: https://doi.org/10.1523/ENEURO.0002-19.2019
Brian B. Griffiths
1Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5117, USA
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Yi-Bing Ouyang
1Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5117, USA
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Lijun Xu
1Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5117, USA
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Xiaoyun Sun
1Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5117, USA
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Rona G. Giffard
1Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5117, USA
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Creed M. Stary
1Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5117, USA
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Abstract

The cellular and molecular mechanisms regulating post-injury neurogenesis in the adult hippocampus remain undefined. We have previously demonstrated that pre-injury treatment with anti-microRNA-181a preserved neurons and prevented astrocyte dysfunction in the hippocampal CA1 following transient forebrain ischemia. In the present study we assessed post-injury treatment with anti-miR-181a on recovery of CA1 neurons following transient forebrain ischemia in rats. Stereotactic CA1 injection of miR-181a antagomir at either 2h or 7d post-injury resulted in improved restoration of CA1 measured at 28d post-injury. Treatment with antagomir was associated with overexpression of the mir-181a target cell-adhesion associated/related oncogene (CDON) protein and enhanced expression of the neuroprogenitor cell marker doublecortin (DCX) in the CA1. Assessment of GFAP+ cell fate by Cre/Lox-mediated deletion demonstrated that some GFAP+ cells in CA1 exhibited de novo DCX expression in response to injury. In vitro experiments using primary neuronal stem cells confirmed that miR-181a inhibition augmented expression of DCX and directed cellular differentiation towards a neuronal fate. These results suggest that miR-181a inhibition plays a central role in restoration of CA1 neurons via augmentation of early latent neurogenic gene activation in neuralprogenitor cells, including some reactive astrocytes. Therapeutic interventions targeting this restorative process may represent a novel post-injury approach to improve clinical outcomes in survivors of forebrain ischemia.

Significance Statement Persistent cognitive impairment is a major source of decreased quality of life for survivors of cardiac arrest, with impaired memory cited as the most severe long-term deficit (Moulaert et al., 2009). Interruptions in cerebral blood flow result in delayed death of hippocampal CA1 neurons (Horn and Schlote, 1992). Pharmaceutical therapies given during this two-week therapeutic window could drastically reduce the cognitive deficits experienced by survivors of forebrain ischemia. However, interventions that have attempted to directly target neurons after forebrain ischemia have so far failed to translate to effective therapies. Therefore, there is an urgent need for novel treatments that either provide protection against loss or hasten functional recovery of CA1 neurons.

  • Astrocytes
  • Forebrain Ischemia
  • Hippocampus
  • MicroRNA
  • Neurogenesis

Footnotes

  • The authors declare no competing financial interests.

  • This study was funded in part by American Heart Association grant #18POST33990395 to BBG, NIH grants NS084396 and NS080177 to RGG, American Heart Association grant FTF-19970029 to CMS.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Post-injury inhibition of miR-181a promotes restoration of hippocampal CA1 neurons after transient forebrain ischemia in rats
Brian B. Griffiths, Yi-Bing Ouyang, Lijun Xu, Xiaoyun Sun, Rona G. Giffard, Creed M. Stary
eNeuro 19 August 2019, ENEURO.0002-19.2019; DOI: 10.1523/ENEURO.0002-19.2019

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Post-injury inhibition of miR-181a promotes restoration of hippocampal CA1 neurons after transient forebrain ischemia in rats
Brian B. Griffiths, Yi-Bing Ouyang, Lijun Xu, Xiaoyun Sun, Rona G. Giffard, Creed M. Stary
eNeuro 19 August 2019, ENEURO.0002-19.2019; DOI: 10.1523/ENEURO.0002-19.2019
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Keywords

  • astrocytes
  • forebrain ischemia
  • hippocampus
  • microRNA
  • neurogenesis

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