Short-term CaMKII inhibition with tatCN19o does not erase pre-formed memory in mice and is neuroprotective in pigs

Nicole L. Rumian, Carolyn Nicole Brown, Tara B. Hendry-Hofer, Thomas Rossetti, James E. Orfila, Jonathan E. Tullis, Linda P. Dwoskin, Olivia R. Buonarati, John E. Lisman, Nidia Quillinan, Paco S. Herson, Vikhyat S. Bebarta, K. Ulrich Bayer

Research output: Contribution to journalArticlepeer-review


The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a central regulator of learning and memory, which poses a problem for targeting it therapeutically. Indeed, our study supports prior conclusions that long-term interference with CaMKII signaling can erase pre-formed memories. By contrast, short-term pharmacological CaMKII inhibition with the neuroprotective peptide tatCN19o interfered with learning in mice only mildly and transiently (for less than 1 h) and did not at all reverse pre-formed memories. These results were obtained with ≥500-fold of the dose that protected hippocampal neurons from cell death after a highly clinically relevant pig model of transient global cerebral ischemia: ventricular fibrillation followed by advanced life support and electrical defibrillation to induce the return of spontaneous circulation. Of additional importance for therapy development, our preliminary cardiovascular safety studies in mice and pig did not indicate any concerns with acute tatCN19o injection. Taken together, although prolonged interference with CaMKII signaling can erase memory, acute short-term CaMKII inhibition with tatCN19o did not cause such retrograde amnesia that would pose a contraindication for therapy.

Original languageEnglish
Article number104693
JournalJournal of Biological Chemistry
Issue number5
StatePublished - May 2023

Bibliographical note

Funding Information:
This work was funded by National Institutes of Health grants T32 GM007635 (supporting C. N. B.), T32 AG000279 (supporting N. L. R.), F31 AG069458 (to N. L. R.), F31 NS129254 (to C. N. B.), F32 AG066536 (to O. R. B.), R01 AG067713 , R01 NS110383 , R01 NS081248 (to K. U. B.), and R01 NS118786 (to K. U. B. and P. S. H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2023 The Authors


  • Ca/calmodulin-dependent protein kinase II (CaMKII)
  • contextual fear conditioning
  • global cerebral ischemia
  • learning
  • memory
  • mouse
  • pig
  • ventricular fibrillation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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