It is widely accepted that cognitive processes, such as learning and memory, are affected in depression, but the molecular mechanisms underlying the interactions of these 2 disorders are not clearly understood. Recently, glycogen synthase kinase-3 beta (GSK-3β)/β-catenin signaling was shown to play an important role in the regulation of learning and memory. The present study used a rat model of depression, chronic unpredictable stress, to determine whether hippocampal GSK-3β/β-catenin signaling was involved in learning and memory alterations. Our results demonstrated that chronic unpredictable stress had a dramatic influence on spatial cognitive performance in the Morris water maze task and reduced the phosphorylation of Ser9 of GSK-3β as well as the total and nuclear levels of β-catenin in the hippocampus. Inhibition of GSK3β by SB216763 significantly ameliorated the cognitive deficits induced by chronic unpredictable stress, while overexpression of GSK3β by AAV-mediated gene transfer significantly decreased cognitive performance in adult rats. In addition, chronic unpredictable stress exposure increased the expression of the canonical Wnt antagonist Dkk-1. Furthermore, chronic administration of corticosterone significantly increased Dkk-1 expression, decreased the phosphorylation of Ser9 of GSK-3β, and resulted in the impairment of hippocampal learning and memory. Our results indicate that impairment of learning and memory in response to chronic unpredictable stress may be attributed to the dysfunction of GSK-3β/β-catenin signaling mediated by increased glucocorticoid signaling via Dkk-1.

It is generally accepted that chronic treatment with antidepressants increases hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. Recently, glycogen synthase kinase-3 beta (GSK-3β)/β-catenin signaling was shown to be involved in the mechanism of how antidepressants might influence hippocampal neurogenesis. The aim of this study was to determine whether GSK-3β/β-catenin signaling is involved in the alteration of neurogenesis as a result of treatment with fluoxetine, a selective serotonin reuptake inhibitor. The mechanisms involved in fluoxetine’s regulation of GSK-3β/β-catenin signaling pathway were also examined. Our results demonstrated that fluoxetine increased the proliferation of embryonic neural precursor cells (NPCs) by up-regulating the phosphorylation of Ser9 on GSK-3β and increasing the level of nuclear β-catenin. The overexpression of a stabilized β-catenin protein (ΔN89 β-catenin) significantly increased NPC proliferation, while inhibition of β-catenin expression in NPCs led to a significant decrease in the proliferation and reduced the proliferative effects induced by fluoxetine. The effects of fluoxetine-induced up-regulation of both phosphorylation of Ser9 on GSK-3β and nuclear β-catenin were significantly prevented by the 5-hydroxytryptamine-1A (5-HT_1A) receptor antagonist WAY-100635. The results demonstrate that fluoxetine may increase neurogenesis via the GSK-3β/β-catenin signaling pathway that links postsynaptic 5-HT_1A receptor activation.

Growing evidence has suggested that elevated Trimethylamine N-oxide (TMAO) levels, a gut microbiota-dependent metabolite, are closely associated with brain aging and cognitive impairment. Glycogen synthase kinase-3 beta (GSK-3β) activity was depicted to be essential in regulating learning and memory. The current study examined the impact of TMAO on cognitive function in mild cognitive impairment (MCI) patients and rat models while exploring the mechanisms regulating the TMAO-induced GSK-3β signaling. This study recruited 115 MCI patients and 128 healthy controls. All participants underwent neuropsychological assessments. Fasting plasma TMAO was measured using high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry. The study also explored whether the GSK-3β signaling was involved in cognitive and function deficits linked with elevated TMAO in rat models. Our results indicated that TMAO plasma levels were elevated in MCI patients compared to healthy controls, depicting a significant association with potential MCI risk. Furthermore, chronic exposure to choline considerably impacted spatial cognitive performance in the Morris water maze task. This reduced the phosphorylation of Ser9 of GSK-3β and the synaptic plasticity-related proteins within the hippocampus, which could be restored by inhibiting TMAO with ABS. In addition, inhibition of GSK-3β by SB216763 significantly prevented the TMAO-induced synaptic damage while decreasing the membrane level of GluA1 and improving hippocampal learning and memory. These results indicate that TMAO can induce hippocampal-dependent learning and memory ability impairment with deficits in synaptic plasticity by regulating the GSK-3β activity.