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 <0.05 in male and 124 + 8.0% vs 208+6.8%, p<0.05 in female). We observed the same magnitude of improvement of LTP at 30 days in male CaMKII Cre/fl mice. Data is currently being collected in female CaMKII Cre/Fl mice. Utilization of an AAV9-Cre administered 7 days post-MCAo significantly rescued LTP; 119+4.3% (n=5) in WT and 176.9 + 9.4% in WT+AAV9-Cre (n=5, p<0.05), demonstrating a sustained benefit of TPRM2 channel deactivation. Our data highlight that TRPM2 channels expressed in neurons contribute to both subacute and chronic dysfunction following transient ischemic stroke.
Coakley et al. (Thu,) studied this question.