CD38 activation of TRPM2 in hippocampal neurons contributes to stroke-induced cognitive dysfunction

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PROJECT SUMMARY Stroke is one of the leading causes of death and disability in the United States. Though the risk of mortality from stroke has declined with advances in reperfusion therapies, the number of survivors developing long-term cognitive impairment has increased with patients experiencing deficits across multiple cognitive domains including short-term memory, executive function and language. While significant research efforts have focused on neuroprotective strategies to reduce infarct volume following ischemic insult, numerous clinical trials showed no improvements functional outcome, despite effective reduction in infarct volume. For this proposal, I consider potential molecular targets for neurorestorative strategies, which aim to restore neural networks perturbed by ischemic injury. I specifically investigate molecular targets which improve Schaffer-CA1 hippocampal long-term potentiation (LTP), one of the mechanisms thought to underlie learning and memory, at both acute and delayed timepoints following stroke. By targeting hippocampal pathways, we aim to reduce the burden of cognitive deficits experienced by numerous patients following ischemic stroke. The transient receptor potential melastatin-related 2 channel (TRPM2) ion channel serves as a promising candidate for pharmacologic intervention post-stroke. TRPM2 is a nonselective cation channel, well-studied due to its sensitivity to oxidative stress and its implication in various central nervous system pathologies. Here, we demonstrate TRPM2 global knockout or pharmacologic inhibition restores hippocampal LTP and hippocampal- dependent learning and memory in a model of transient middle cerebral artery occlusion (MCAO). However, the cell-type specific role of TRPM2 and its mechanism of activation remain largely unknown. In this proposal, I examine the neuronal contribution of TRPM2 to hippocampal synaptic and cognitive impairment in a mouse model of MCAO. I also provide compelling preliminary evidence the ectoenzyme, CD38, is upregulated in astrocytes following MCAO, generating ligand necessary for TRPM2 activation, thereby producing cognitive deficits in both sexes. To further elucidate the cell-specific role of TRPM2 and its mechanism of activation, I propose to employ in vitro and in vivo electrophysiologic, molecular and neurobehavioral approaches. In this proposal, I investigate a novel neuroglial mechanism to uncover potential molecular targets for acute and chronic pharmacologic intervention to reduce the burden of cognitive disability following ischemic stroke.