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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月14日

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  • Hannah M. Jester,
  • Noelle Nicol,
  • Qian Yang,
  • Yankai Zhang,
  • Amelia Suhocki,
  • Xueyan Zhou,
  • Ethan Underwood,
  • Hadi Pourhadi,
  • Dongmei Cheng,
  • Jingyun Lee,
  • Peiqing Sun,
  • Cristina M. Furdui,
  • Christopher G. Proud,
  • Kobi Rosenblum,
  • Tao Ma

摘要

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.