Reversal of Global Ischemia-Induced Cognitive Dysfunction by Delayed Inhibition of TRPM2 Ion Channels

  • Robert M. Dietz
  • Ivelisse Cruz-Torres
  • James E. Orfila
  • Olivia P. Patsos
  • Kaori Shimizu
  • Nicholas Chalmers
  • Guiying Deng
  • Erika Tiemeier
  • Nidia Quillinan
  • Paco S. HersonEmail author
Original Article


Hippocampal injury and cognitive impairments are common after cardiac arrest and stroke and do not have an effective intervention despite much effort. Therefore, we developed a new approach aimed at reversing synaptic dysfunction by targeting TRPM2 channels. Cardiac arrest/cardiopulmonary resuscitation (CA/CPR) in mice was used to investigate cognitive deficits and the role of the calcium-permeable ion channel transient receptor potential-M2 (TRPM2) in ischemia-induced synaptic dysfunction. Our data indicates that absence (TRPM2−/−) or acute inhibition of TRPM2 channels with tatM2NX reduced hippocampal cell death in males only, but prevented synaptic plasticity deficits in both sexes. Remarkably, administration of tatM2NX weeks after injury reversed hippocampal plasticity and memory deficits. Finally, TRPM2-dependent activation of calcineurin-GSK3β pathway contributes to synaptic plasticity impairments. These data suggest persistent TRPM2 activity following ischemia contributes to impairments of the surviving hippocampal network and that inhibition of TRPM2 channels at chronic time points may represent a novel strategy to improve functional recovery following cerebral ischemia that is independent of neuroprotection.


Neurorestoration Synaptic plasticity LTP Cognitive impairment Stroke Cardiac arrest 



We thank Joan Yonchek for her expert assistance with histology preparation and unwavering support.

Author Contributions

Conceptualization: P.S.H.; Methodology: R.M.D, I.C-T, J.E.O., N.Q., P.S.H.; Investigation: R.M.D., I.C-T, J.E.O., O.P.P., K.S., N.C., G.D., E.T; Writing original draft: R.M.D. and I.C-T.; Writing, reviewing, and editing: R.M.D., I.C-T., J.E.O., N.Q., P.S.H., Funding acquisition: R.M.D., P.S.H.

Funding Information

This study was funded by extramural grant support. This research was supported by National Institutes of Health grants T32GM007635 (Pharmacology training grant), K08NS097586 (R.M.D), and R01NS092645 (P.S.H).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable national and institutional guidelines for the care and use of animals were followed. Ethical approval: This article does not contain any studies with human participants.

Supplementary material

12975_2019_712_MOESM1_ESM.docx (193 kb)
ESM 1 (DOCX 193 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Robert M. Dietz
    • 1
    • 2
  • Ivelisse Cruz-Torres
    • 2
    • 3
  • James E. Orfila
    • 2
    • 4
  • Olivia P. Patsos
    • 2
    • 4
  • Kaori Shimizu
    • 2
    • 4
  • Nicholas Chalmers
    • 2
    • 4
  • Guiying Deng
    • 2
    • 4
  • Erika Tiemeier
    • 2
    • 4
  • Nidia Quillinan
    • 2
    • 4
  • Paco S. Herson
    • 2
    • 3
    • 4
    Email author
  1. 1.Department of PediatricsUniversity of Colorado School of MedicineAuroraUSA
  2. 2.Neuronal Injury & Plasticity ProgramUniversity of Colorado School of MedicineAuroraUSA
  3. 3.Department of PharmacologyUniversity of Colorado School of MedicineAuroraUSA
  4. 4.Department of AnesthesiologyUniversity of Colorado School of MedicineAuroraUSA

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