Tuesday, February 4, 2025
2/4/2025
Project Summary/Abstract The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a central mediator of two opposing forms of NMDA- receptor (NMDAR)-dependent synaptic plasticity: long-term potentiation (LTP) and depression (LTD). Pathological overstimulation of NMDARs during cerebral ischemia causes excitotoxic neuronal cell death, and we have recently shown that CaMKII mediates also the neuronal damage after global cerebral ischemia (GCI). Importantly, in vivo injection of our optimized CaMKII inhibitor (tatCN19o) provided significant neuroprotection after GCI models that closely mimic the most relevant human conditions: cardiopulmonary resuscitation (CPR) after cardiac arrest in mice or after ventricular fibrillations in pig (unpublished). CaMKII inhibition (i) was done at a highly clinically relevant timepoint for these conditions (30 min after CPR); (ii) was effective also in conjunction with current standard of care (therapeutic hypothermia); and (iii) protected not only from neuronal cell death but also from the long-lasting functional impairments in LTP that are seen in the surviving neurons. Here, three connected but independent aims will directly promote, our mechanistic understanding of CaMKII- mediated regulation of neuronal cell death and LTP impairment. Specifically, the project will investigate (1) the cross-talk of CaMKII autonomy mechanisms in mediating ischemia-induced neuronal damage, (2) a possible dual role of CaMKII in neuronal cell death versus survival, and (3) mechanisms that underly the CaMKII- dependent long-term LTP impairment of the neurons that survive after ischemia. Together, the results of this study will significantly advance our understanding of the molecular mechanisms underlying ischemic neuronal cell death. Additionally, they will inform future development of a therapy in humans.
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