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

• DOI: 10.1007/s12975-019-00712-z
• Publication Date: 2019-06-27T23:04:16Z
• Authors: 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
• Keywords: Male; Mice, Knockout; Neurons; 0301 basic medicine; Glycogen Synthase Kinase 3 beta; Neuronal Plasticity; Calcineurin; TRPM Cation Channels; Hippocampus; Cardiopulmonary Resuscitation; Heart Arrest; 03 medical and health sciences; Ischemia; Animals; Cognitive Dysfunction; Female

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.