Eukaryotic initiation factor 4E: a key factor of traumatic stress-induced depression-related cognitive decline at different age

Depression in patients with cognitive impairment may be a risk factor for dementia. A previous study demonstrated that patients with treatment-resistant depression (TRD), characterized by poor response to adequate antidepressant treatment, exhibit pronounced cognitive impairment. Although depression in midlife or later life are associated with an increased risk of developing dementia, the mechanisms linking cognitive impairment and midlife depression remain poorly understood. A recent study revealed that downregulation of the γ-aminobutyric acid mediated (GABAergic) system and increased phosphorylation of eukaryotic translation initiation factor (eIF4E) are strongly associated with cognitive dysfunction and depressive symptoms. Hence, we hypothesized that the GABAergic system and eIF4E phosphorylation are involved in cognitive dysfunction and depression, particularly forms resistant to treatment, with increased aging. In the present study, we used a mouse model exhibiting antidepressant-resistant symptoms induced by traumatic stress in young- and middle-aged mice. Depression-like behavior was observed after traumatic stress exposure in both young and middle-aged mice. However, cognitive impairment induced by traumatic stress was worse in middle-aged mice. Moreover, the expression of GABA_A and GABA_B receptors decreased after traumatic stress exposure in both young and middle-aged mice. However, the increase in eIF4E phosphorylation was greater after traumatic stress exposure in the middle-aged mice. Depressive-like behavior was improved by inhibition of eIF4E phosphorylation and GABA receptor activation, whereas cognitive impairment was only improved by inhibition of eIF4E phosphorylation. These findings suggest that eIF4E plays a key role in age-related cognitive dysfunction and depression.