Abstract DP267: PSCI improved when targeting TRPM2 channel in neurons

Background: Emerging evidence implicates Post-Stroke Cognitive Impairment (PSCI) as a major contributor to long-term disability. Therefore, optimal therapeutic will need to reduce acute ischemic injury and enhance post-stroke brain function. Strong data demonstrates that the transient receptor potential melastatin 2 (TRPM2) channel activity worsens post-stroke deficits. Here, we test the hypothesis that reducing the expression level of TRPM2 channel specifically within neurons improves cognitive function at the sub-acute and chronic stages. Methods: Transient Middle Cerebral Artery occlusion (MCAo) was performed on adult male and female TRPM2 neuron-specific KO (CaMKII Cre/Fl ), TRPM2 floxed controls, and Wild Type (WT) mice. Hemispheric infarct volume analyzed from MRI (T2) images 3 days post-injury by a blinded investigator. AAV9-CamKII-cre-GFP was administered 7 days post-stroke in TRPM2 fl/fl mice. The TRPM2 antagonist, tat-M2NX, was administered 29 days post injury, IV, in WT mice. Extracellular field recordings of CA1 neurons were performed in hippocampal slices to assess long-term potentiation (LTP), a cellular model of learning and memory. Additionally, contextual fear conditioning (CFC) behavioral paradigm was performed as a measure of hippocampal dependent memory. Results: Neuron-specific TRPM2 male and female knockout mice had equal magnitude infarct volume compared to WT mice (Male: KO: 21.11+5.99%, WT: 33.63+6.67%, p=.80; Female KO: 27.27+7.03%, WT: 34.23+7.19%, p=.98). As previously reported, we observed impaired LTP in control (TRPM2 fl/fl and WT) mice 7 and 30 days after 60 min MCAO. Consistent with the hypothesis that neuronal TRPM2 channels contribute to ischemia-induced synaptic dysfunction, recordings obtained in brain slices from male or female CaMKII Cre/Fl mice 7 post-MCAo exhibited improved hippocampal plasticity compared to control mice (147+1.0% vs 191+12.1%, p