Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, P.R. China.
Department of Pharmacology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu 210023, P.R. China.
Theranostics. 2022 Sep 11;12(15):6611-6625. doi: 10.7150/thno.77455. eCollection 2022.
Astrocyte dysfunction is one of the important pathological mechanisms of depression. Stress contributes to the onset of depression. As metabolic stress sensor, Kir6.1-contaning K-ATP channel (Kir6.1/K-ATP) is prominently expressed in astrocytes. However, the involvement of Kir6.1/K-ATP channel in depression remains obscure. Astrocyte-specific Kir6.1 knockout mice were used to prepare two mouse models of depression to explore the role of astrocytic Kir6.1/K-ATP channel in depression. Primary astrocytes were cultured to reveal the underlying mechanism for Kir6.1-regulated astrocytic pyroptosis. We identified that chronic stress reduced the astrocytic Kir6.1 expression in hippocampus of mice. We further observed astrocyte-specific knockout of Kir6.1 induced depressive-like behaviors in mice. Moreover, we found that astrocytic Kir6.1 deletion increased NLRP3-mediated astrocytic pyroptosis in response to stress. Mechanistically, Kir6.1 associated with NLRP3, and this interaction prevented the assembly and activation of NLRP3 inflammasome, thereby inhibition of astrocytic pyroptosis. More importantly, VX-765, an effective and selective inhibitor for NLRP3 inflammasome, could reverse the astrocytic pyroptosis and rescue the deterioration of behaviors in astrocytic Kir6.1 knockout mice. Our findings illustrate that Kir6.1/K-ATP channel in astrocytes is an essential negative modulator of astrocytic pyroptosis and plays a crucial role in depression and suggest that astrocytic Kir6.1/K-ATP channel may be a promising therapeutic target for depression.
星形胶质细胞功能障碍是抑郁症的重要病理机制之一。应激是导致抑郁症发生的原因之一。作为代谢应激传感器，Kir6.1 包含的 K-ATP 通道（Kir6.1/K-ATP）在星形胶质细胞中表达明显。然而，Kir6.1/K-ATP 通道在抑郁症中的作用仍不清楚。本研究使用星形胶质细胞特异性 Kir6.1 敲除小鼠制备了两种抑郁症小鼠模型，以探讨星形胶质细胞 Kir6.1/K-ATP 通道在抑郁症中的作用。培养原代星形胶质细胞以揭示 Kir6.1 调节星形胶质细胞细胞焦亡的潜在机制。研究发现慢性应激降低了小鼠海马体星形胶质细胞的 Kir6.1 表达。进一步观察到星形胶质细胞特异性 Kir6.1 敲除诱导了小鼠的抑郁样行为。此外，研究发现星形胶质细胞 Kir6.1 缺失增加了 NLRP3 介导的应激时星形胶质细胞细胞焦亡。机制上，Kir6.1 与 NLRP3 相关，这种相互作用阻止了 NLRP3 炎性小体的组装和激活，从而抑制了星形胶质细胞细胞焦亡。更重要的是，NLRP3 炎性小体的有效和选择性抑制剂 VX-765 可逆转星形胶质细胞细胞焦亡，并挽救星形胶质细胞 Kir6.1 敲除小鼠行为的恶化。研究结果表明，星形胶质细胞中的 Kir6.1/K-ATP 通道是星形胶质细胞细胞焦亡的重要负调节因子，在抑郁症中起关键作用，并提示星形胶质细胞 Kir6.1/K-ATP 通道可能是治疗抑郁症的有希望的靶点。
