Inhibitors of cellular stress overcome acute effects of ethanol on hippocampal plasticity and learning

Ethanol intoxication can produce marked changes in cognitive function including states in which the ability to learn and remember new information is completely disrupted. These defects likely reflect changes in the synaptic plasticity thought to underlie memory formation. We have studied mechanisms contributing to the adverse effects of ethanol on hippocampal long-term potentiation (LTP) and provided evidence that ethanol-mediated LTP inhibition involves a form of metaplasticity resulting from local metabolism of ethanol to acetaldehyde and untimely activation of N-methyl-D-aspartate receptors (NMDARs), both of which are neuronal stressors. In the present studies, we sought to understand the role of cellular stress in LTP defects, and demonstrate that ethanol's effects on LTP in the CAl hippocampal region are overcome by agents that inhibit cellular stress responses, including ISRIB, a specific inhibitor of integrated stress responses, and GW3965, an agonist that acts at liver X receptors (LXRs) and dampens cellular stress. The agents that alter LTP inhibition also prevent the adverse effects of acute ethanol on one trial inhibitory avoidance learning. Unexpectedly, we found that the LXR agonist but not ISRIB overcomes effects of ethanol on synaptic responses mediated by Nmethyl-D-aspartate receptors (NMDARs). These results have implications for understanding the adverse effects of ethanol and possibly for identifying novel paths to treatments that can prevent or overcome ethanol-induced cognitive dysfunction.