Journal
TRANSLATIONAL STROKE RESEARCH
Volume 11, Issue 2, Pages 254-266Publisher
SPRINGER
DOI: 10.1007/s12975-019-00712-z
Keywords
Neurorestoration; Synaptic plasticity; LTP; Cognitive impairment; Stroke; Cardiac arrest
Categories
Funding
- Nation Institutes of Health [K08NS097586] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007635] Funding Source: Medline
- NIH HHS [R01NS092645, T32GM007635] Funding Source: Medline
- NINDS NIH HHS [K08 NS097586, R01 NS092645] Funding Source: Medline
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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-GSK3 beta 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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