Overactive Neuronal eEF2K/eEF2 signaling is associated with cognitive impairment and apathy-like behavior

Résumé fourni par la source

Dysregulated protein synthesis has been implicated in multiple neurodevelopmental, neurodegenerative, and neuropsychiatric diseases. Protein synthesis or mRNA translation is critically regulated through phosphorylation of eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K. Increased eEF2K activity leads to elevated phosphorylation and inhibition of eEF2 and inhibits the elongation phase of protein synthesis. Recent studies suggest a link between eEF2 hyper-phosphorylation and several neuronal diseases characterized by cognitive impairments. Phosphorylation of eEF2 by eEF2K has also been implicated as a molecular mechanism for the rapid antidepressant effect of ketamine. Whether there exists a causal relationship between overactive eEF2K/eEF2 signaling and impaired synaptic and cognitive function remains unknown. To fill this critical knowledge gap, we generated a transgenic mouse model (eEF2K-cKI) overexpressing eEF2K in excitatory neurons to investigate how eEF2K/eEF2 signaling can impact cognitive functions and neuropsychiatric behaviors. We assessed hippocampal-dependent learning and memory, as well as multiple neuropsychiatric domains associated with a depressive phenotype including despair, anhedonia, apathy, anxiety, and sociability. The eEF2K-cKI mice exhibit learning and memory impairments, and robust apathy-like phenotype without other despair/depression-like behaviors. We also found impaired long-term potentiation and altered dendritic spine and synaptic morphology in the hippocampus of the eEF2K-cKI mice. Proteomic analysis revealed changes in levels of proteins associated with neuropsychiatric and neurodegenerative disorders. Our findings present direct evidence supporting the pathophysiological role of aberrant eEF2K/eEF2 signaling in brain function and help provide insight into novel mechanisms and therapeutic avenues for neuronal diseases characterized by dementia and neuropsychiatric symptoms.

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