Sustained AMP-activated Protein Kinase Activation Attenuates the Activity of Brain-derived Neurotrophic Factor/Tyrosine Kinase Receptor B Signaling in Mice Exposed to Chronic Stress
Major depressive disorder (MDD) is one of the leading causes of disability worldwide, with a complex molecular pathophysiology that has attracted significant attention. The neurotrophic hypothesis of depression suggests that brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), play a critical role in neurogenesis and synaptogenesis, processes essential for the effects of antidepressants. BDNF/TrkB signaling activates downstream pathways that promote cell survival, which is crucial for maintaining neuronal plasticity and function. Beyond its role in neuronal growth, BDNF also regulates systemic metabolism. Blockade of BDNF/TrkB signaling in the periphery has been shown to downregulate metabolic molecules, including AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis.
The relationship between AMPK and BDNF/TrkB signaling in the context of depression remains poorly understood. While some studies indicate that chronic stress, lipopolysaccharide (LPS), and corticosterone reduce AMPK phosphorylation in the brain, others suggest that sustained AMPK activation contributes to depression induced by chronic corticosterone. This discrepancy highlights the need for further investigation into the role of AMPK in depression. The present study aimed to elucidate the interaction between BDNF/TrkB signaling and AMPK in chronic stress-induced depression and to determine whether BDNF/TrkB signaling functions in an AMPK-dependent manner.
To explore these questions, the researchers used 7,8-dihydroxyflavone, a TrkB agonist, to activate BDNF/TrkB signaling and evaluated its effects on depressive-like behaviors, neurogenesis, and synaptogenesis in mice exposed to chronic stress. They also employed pharmacological interventions, including TrkB antagonists and AMPK inhibitors/activators, to assess changes in behavior and molecular signaling pathways.
The study first evaluated the effects of 7,8-dihydroxyflavone on depressive-like behaviors. Chronic stress induced a decrease in sucrose preference, prolonged latency to feed, and increased immobility time, all of which were reversed by treatment with 7,8-dihydroxyflavone (10 mg/kg, intraperitoneally). These behavioral improvements were accompanied by restoration of BDNF expression, TrkB phosphorylation, and AMPK phosphorylation, which were significantly reduced by chronic stress. Additionally, 7,8-dihydroxyflavone reversed the inhibition of doublecortin (DCX)-positive cells and dendritic spine density in the hippocampus, indicators of neurogenesis and synaptogenesis, respectively.
To determine whether the effects of 7,8-dihydroxyflavone were mediated by TrkB activation, mice were co-treated with K252a, a selective TrkB antagonist. K252a (25 mg/kg) completely abolished the antidepressant-like effects of 7,8-dihydroxyflavone, as well as its enhancement of BDNF, TrkB, and AMPK signaling. Furthermore, the increases in DCX-positive cells and dendritic spine density induced by 7,8-dihydroxyflavone were blocked by K252a. These findings confirm that the antidepressant-like effects of 7,8-dihydroxyflavone are dependent on TrkB activation.
Next, the study investigated whether AMPK signaling is required for the antidepressant-like effects of TrkB activation. Mice were pretreated with Compound C, an AMPK inhibitor, before receiving 7,8-dihydroxyflavone. Surprisingly, Compound C did not alter the behavioral improvements induced by 7,8-dihydroxyflavone, such as increased sucrose preference and reduced immobility time. While Compound C effectively inhibited AMPK phosphorylation, it did not affect the enhancement of BDNF and TrkB expression by 7,8-dihydroxyflavone. These results suggest that AMPK is not required for the antidepressant-like effects of TrkB activation.
The study also examined downstream signaling pathways modulated by BDNF/TrkB, including the mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3 beta (GSK3b)/cAMP responsive element binding (CREB) pathways. Both pathways are regulated by Akt, a downstream effector of BDNF/TrkB signaling. The researchers found that mTOR phosphorylation was activated by 7,8-dihydroxyflavone and Compound C, and co-treatment with both compounds maintained mTOR activation. However, the effects of 7,8-dihydroxyflavone on GSK3b/CREB signaling were partially blocked by Compound C, while Akt phosphorylation remained activated. Immunofluorescence and Golgi staining confirmed that Compound C did not alter the effects of 7,8-dihydroxyflavone on DCX-positive cells and dendritic spine density. These findings suggest that AMPK negatively regulates mTOR signaling but positively regulates GSK3b/CREB signaling.
To further explore the role of AMPK, the researchers used aminoimidazole carboxamide ribonucleotide (AICAR), an AMPK activator. AICAR treatment alone did not induce antidepressant-like effects but abolished the behavioral improvements induced by 7,8-dihydroxyflavone. AICAR increased AMPK phosphorylation and upregulated GSK3b/CREB signaling. When co-treated with 7,8-dihydroxyflavone, AICAR inhibited BDNF expression, TrkB phosphorylation, and mTOR activation. Immunofluorescence and Golgi staining revealed that AICAR blocked the effects of 7,8-dihydroxyflavone on dendritic spine density, indicating that sustained AMPK activation impairs BDNF/TrkB signaling.
The study’s findings suggest that BDNF/TrkB signaling induces antidepressant-like effects in an AMPK-independent manner in chronic stress. However, sustained AMPK activation attenuates BDNF/TrkB signaling by inhibiting mTOR, which directly impairs protein synthesis and leads to deficiencies in neurogenesis and synaptogenesis. These results highlight the complex role of AMPK in depression and suggest that while temporary AMPK activation may be beneficial, sustained hyperactivity can have detrimental effects on neuronal function.
In conclusion, this study provides new insights into the interaction between BDNF/TrkB signaling and AMPK in chronic stress-induced depression. It demonstrates that BDNF/TrkB signaling exerts antidepressant-like effects independently of AMPK and that sustained AMPK activation impairs BDNF/TrkB signaling by inhibiting mTOR. These findings underscore the importance of carefully considering the timing and duration of AMPK activation in the development of therapeutic strategies for depression.
doi.org/10.1097/CM9.0000000000001323
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