Esketamine-mediated alleviation of electroconvulsive shock-induced memory impairment is associated with the regulation of mGluR5 in depressive-like rats

Electroconvulsive therapy (ECT) is recognized as one of the most efficacious interventions for depression. However, it is associated with impairments in learning and memory functions. Ketamine has demonstrated potential in mitigating cognitive deficits. Notably, the metabotropic glutamate system is hypothesized to play a pivotal role in cognitive process regulation. Nevertheless, the involvement of the metabotropic glutamate system in esketamine-mediated alleviation of electroconvulsive shock (ECS, an animal analogue of ECT)-induced memory impairment remains to be elucidated. In this study, a depressive rat model was established using chronic unpredictable mild stress. The depressive-like behavior and cognitive performance of the rats were evaluated using the sucrose preference test, the open field test, and the Morris water maze test, respectively. The expression levels of type-5 metabotropic glutamate receptor (mGluR5) and N-methyl-d-aspartate receptor 1 (NMDAR1) were quantified through immunofluorescence and real-time PCR techniques. Long-term potentiation (LTP) of hippocampal Schaffer collateral (SC)-CA1 synapses was observed in electrophysiological experiments. The results of this investigation revealed that a low dose of esketamine administration upregulated the expression of mGluR5 and NMDAR1 in the hippocampus of stressed rats, alleviated ECS-induced cognitive impairment, and ameliorated depressive-like behavior. Conversely, the mGluR5 antagonist MTEP effectively reversed esketamine-mediated changes in the rat hippocampus and counteracted its protective effect on learning and memory functions following ECS. In conclusion, the findings of this study support the hypothesis that esketamine upregulates mGluR5 and NMDAR1 expression, thereby enhancing NMDAR activation in the hippocampus. This mechanism may be responsible for the protective effects on spatial learning and memory function observed in depressed rats subjected to ECS.