Abstract W P96: Evidence of In Vivo Ischemic LTP Caused by Cardiac Arrest and Cardiopulmonary Resuscitation

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Objective: Experience-dependent memory acquisition, in vitro tetanic stimulation and simulated ischemia results in long-term potentiation (LTP) of hippocampal CA1 synapses. The goal of this study was to determine whether in vivo cerebral ischemia results in iLTP of CA1 synapses. We hypothesized that iLTP resulting from CA/CPR prevents physiological LTP. Methods: Cardiac arrest (8 minutes) followed by cardiopulmonary resuscitation (CA/CPR) or sham surgery was performed on adult (8-12 week) male mice. Electrophysiology was performed in hippocampal slices from sham and 7 and 30 days after CA/CPR. Field excitatory postsynaptic potentials (fEPSP) resulting from Schaffer collateral stimulation were recorded and rising slope was analyzed. Theta burst stimulation (TBS) was used for LTP induction and low frequency stimulation for reversal of LTP (depotentiation). Western blot analysis of synaptic isolations were performed from hippocampi collected from shams and 7 and 30 days after CA/CPR. Results: TBS resulted in an increased fEPSP to 164±9.8% (n=7, P<0.05) of baseline in sham controls, however no increase was observed at 7 (106±15.9% n=4) and 30 days (109±13.9% n=7) after CA/CPR. A depotentiation stimulus had no effect in sham controls, but caused a reduction in fEPSP in control slices that received LTP induction and slices from CA/CPR mice. Importantly, LTP induction protocol applied subsequent to depotentiation stimulus resulted in physiological LTP to 126.9±11.8% (n=3) of the original baseline, an effective increase of approximately 40%. Glutamate receptor subunit GluR1 phosphorylation and expression in synaptic fractions were increased at 7 and 30 days after CA/CPR. Conclusions: Depotentiation in slices from CA/CPR mice suggests CA1 synapses are in a chronically potentiated state. Increased GluR1 phosphorylation and expression after CA/CPR also suggest in vivo ischemia causes iLTP. Our ability to induce physiological LTP after depotentiation in slices from CA/CPR suggests that reversing iLTP allows for normal synaptic plasticity. The results of this study are significant as they demonstrate in vivo iLTP and suggest a physiological stimulus has the potential to reverse synaptic impairments in the chronic phase after cerebral ischemia.