Activation of astrocytic sigma-1 receptor exerts antidepressant-like effect via facilitating CD38-driven mitochondria transfer.,Glia

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Activation of astrocytic sigma-1 receptor exerts antidepressant-like effect via facilitating CD38-driven mitochondria transfer.
Glia ( IF 5.4 ) Pub Date : 2020-05-27 , DOI: 10.1002/glia.23850
Yun Wang ₁ , Jing Ni ₁ , Tianyu Gao ₁ , Ce Gao ₁ , Lin Guo ₁ , Xiaoxing Yin ₁

Affiliation

Despite sigma‐1 receptor (Sig‐1R) is a promising therapeutic target in depression, little is known regarding the cellular mechanisms underlying its antidepressant responses. Here, we demonstrated that astrocyte can be a direct cellular target of Sig‐1R exerting antidepressant‐like effect. In multiple behavioral models including forced swimming test (FST), tail suspension test (TST), open field test (OFT), and chronic unpredictable mild stress (CUMS), inhibition of astrocyte function blocked pharmacological Sig‐1R activation‐induced antidepressant‐like effect, while specific activation of astrocytc Sig‐1R by adeno‐associated virus (AAV) was sufficient to produce antidepressant‐like effect. In depression‐related cellular tests, Sig‐1R agonist or lentivirus‐stimulated astrocyte conditioned medium (ACM) promoted neuronal neurite outgrowth, dendritic branch, and survival. Mechanismly, stimulation of Sig‐1R enhanced the expression of CD38 via activation of extracellular regulated protein kinases 1/2 (ERK1/2), resulting in facilitating mitochondrial transfer from astrocyte. Furthermore, blockage of CD38‐driven astrocyte transferring mitochondria in vivo and in vitro reversed the antidepressant‐like effect of pharmacological Sig‐1R activation. Thus, this study sheds light on the cellular mechanism of Sig‐1R activation producing antidepressant‐like effect. These data present the first evidence that enhancement of Sig‐1R action on astrocytes entirely exerts antidepressant‐like effect, indicating that specific activation of astrocytic Sig‐1R may provide a new approach for antidepressant drug development.

中文翻译：

星形细胞 sigma-1 受体的激活通过促进 CD38 驱动的线粒体转移发挥抗抑郁样作用。

尽管 sigma-1 受体 (Sig-1R) 是抑郁症的一个有前途的治疗靶点，但对其抗抑郁反应背后的细胞机制知之甚少。在这里，我们证明星形胶质细胞可以成为 Sig-1R 的直接细胞靶标，发挥抗抑郁样作用。在包括强迫游泳试验（FST）、悬尾试验（TST）、旷场试验（OFT）和慢性不可预测轻度应激（CUMS）在内的多种行为模型中，星形胶质细胞功能的抑制阻断了药理学Sig-1R激活诱导的抗抑郁样药物腺相关病毒（AAV）对星形胶质细胞 Sig-1R 的特异性激活足以产生抗抑郁样作用。在抑郁症相关的细胞测试中，Sig-1R 激动剂或慢病毒刺激的星形胶质细胞条件培养基 (ACM) 促进神经元神经突生长、树突分支和存活。从机制上来说，刺激 Sig-1R 通过激活细胞外调节蛋白激酶 1/2 (ERK1/2) 增强 CD38 的表达，从而促进星形胶质细胞的线粒体转移。此外，在体内和体外阻断 CD38 驱动的星形胶质细胞转移线粒体，逆转了药理学 Sig-1R 激活的抗抑郁样作用。因此，这项研究揭示了 Sig-1R 激活产生抗抑郁样作用的细胞机制。这些数据首次证明Sig-1R对星形胶质细胞作用的增强完全发挥抗抑郁样作用，表明星形胶质细胞Sig-1R的特异性激活可能为抗抑郁药物的开发提供新方法。

更新日期：2020-05-27

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