Abstract
Astrocytic glycogen plays an important role in brain energy metabolism. However, the contribution of glycogen metabolism to stress-induced depression remains unclear. Chronic social defeat stress was used to induce depression-like behaviors in mice, assessed with behavioral tests. Glycogen concentration in the medial prefrontal cortex (mPFC) and the expression of key enzymes of the glycogen metabolism were investigated using Western blots, immunofluorescent staining, electron microscopy, and biochemical assays. Stereotaxic surgery and viral-mediated gene transfer were applied to knockdown or overexpress brain-type glycogen phosphorylase (PYGB) in the mPFC. The glycogen content increased in the mPFC after stress. Glycogenolytic dysfunction due to inactivation of PYGB was responsible for glycogen accumulation. Behavioral tests on astrocyte-specific PYGB overexpression mice showed that augmenting astrocytic PYGB reduces susceptibility to depression when compared with stress-susceptible mice. Conversely, PYGB genetic down-regulation in the mPFC was sufficient to induce glycogen accumulation and depression-like behaviors. Furthermore, PYGB overexpression in the mPFC decreases susceptibility to depression, at least partially by rescuing glycogen phosphorylase activity to maintain glycogen metabolism homeostasis during stress. These findings indicate that (1) glycogen accumulation occurs in mice following stress and (2) glycogenolysis reprogramming leads to glycogen accumulation in astrocytes and PYGB contributes to stress-induced depression-like behaviors. Pharmacological tools acting on glycogenolysis might constitute a promising therapy for depression.
Highlights
The global prevalence of depression is increasing, causing a tremendous economic burden (Menard et al, 2016)
We examined the behavioral effect of chronic social defeat stress (CSDS), and measured the glycogen concentration in the medial prefrontal cortex and the level of important enzymes of glycogen metabolism in stresssusceptible (SS) mice
To explore the intermediary components modulated by neurometabolism and stress, we exposed male C57BL/6J mice to 10 days of CSDS to mimic depression
Summary
The global prevalence of depression is increasing, causing a tremendous economic burden (Menard et al, 2016). Despite the often complete remission with current antidepressant treatment, serious side effects are common and patients require long-term therapy (Johnston et al, 2019). A disturbed monoamine transmission is considered to be involved in the pathogenesis of depression. Growing evidence suggests that the hypothalamic-pituitary-adrenal axis and proinflammatory cytokines play important roles (Hayley et al, 2021; Qin et al, 2021). The fact that current treatment strategies are not useful in some patients evidences our incomplete understanding of the disease etiology. New theories are needed to improve treatment and clinical outcomes
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