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.
