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

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Abstract

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.

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Acknowledgments

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

Funding

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).

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Author notes

  1. Robert M. Dietz and Ivelisse Cruz-Torres contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA

    Robert M. Dietz

  2. Neuronal Injury & Plasticity Program, University of Colorado School of Medicine, Aurora, CO, USA

    Robert M. Dietz, Ivelisse Cruz-Torres, James E. Orfila, Olivia P. Patsos, Kaori Shimizu, Nicholas Chalmers, Guiying Deng, Erika Tiemeier, Nidia Quillinan & Paco S. Herson

  3. Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA

    Ivelisse Cruz-Torres & Paco S. Herson

  4. Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO, USA

    James E. Orfila, Olivia P. Patsos, Kaori Shimizu, Nicholas Chalmers, Guiying Deng, Erika Tiemeier, Nidia Quillinan & Paco S. Herson

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  1. Robert M. Dietz
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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.

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Correspondence to Paco S. Herson.

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Dietz, R.M., Cruz-Torres, I., Orfila, J.E. et al. Reversal of Global Ischemia-Induced Cognitive Dysfunction by Delayed Inhibition of TRPM2 Ion Channels. Transl. Stroke Res. 11, 254–266 (2020). https://doi.org/10.1007/s12975-019-00712-z

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