The role of ventral hippocampus (vHipp) astroglial gliotransmission in depression was studied using chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) rodent models. CRS increased Cx43 hemichannel activity and extracellular glutamate levels in the vHipp and blocking astroglial Cx43 hemichannel-dependent gliotransmission during CRS prevented the development of depression and glutamate buildup. Moreover, the acute blockade of Cx43 hemichannels induced antidepressant effects in rats previously subjected to CRS or CUMS. This antidepressant effect was prevented by coinjection of glutamate and D-serine. Furthermore, Cx43 hemichannel blockade decreased postsynaptic NMDAR currents in vHipp slices in a glutamate and D-serine-dependent manner. Notably, chronic microinfusion of glutamate and D-serine, L-serine, or the NMDAR agonist NMDA, into the vHipp induced depressive-like symptoms in nonstressed rats. We also identified a small molecule, cacotheline, which blocks Cx43 hemichannels and its systemic administration induced rapid antidepressant effects, preventing stress-induced increases in astroglial Cx43 hemichannel activity and extracellular glutamate in the vHipp, without sedative or locomotor side effects. In conclusion, chronic stress increases Cx43 hemichannel-dependent release of glutamate and D-/L-serine from astrocytes in the vHipp, overactivating postsynaptic NMDARs and triggering depressive-like symptoms. This study highlights the critical role of astroglial gliotransmitter release in chronic stress-induced depression and suggests it can be used as a target for the prevention and treatment of depression.

中文翻译：

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星形胶质细胞在抑郁症中的作用、预防和通过靶向星形胶质细胞胶质递质释放进行治疗


使用慢性约束应激 （CRS） 和慢性不可预测的轻度应激 （CUMS） 啮齿动物模型研究了腹侧海马 （vHipp） 星形胶质细胞胶质细胞传递在抑郁症中的作用。CRS 增加了 vHipp 中的 Cx43 半通道活性和细胞外谷氨酸水平，并在 CRS 期间阻断星形胶质细胞 Cx43 半通道依赖性胶质细胞传递，防止了抑郁和谷氨酸积累的发展。此外，Cx43 半通道的急性阻断在先前接受 CRS 或 CUMS 的大鼠中诱导了抗抑郁作用。这种抗抑郁作用是通过共同注射谷氨酸和 D-丝氨酸来阻止的。此外，Cx43 半通道阻断以谷氨酸和 D-丝氨酸依赖性方式降低 vHipp 切片中突触后 NMDAR 电流。值得注意的是，将谷氨酸和 D-丝氨酸、L-丝氨酸或 NMDAR 激动剂 NMDA 长期微输注到 vHipp 中会诱导非应激大鼠的抑郁样症状。我们还鉴定了一种小分子 cacotheline，它阻断 Cx43 半通道，其全身给药诱导快速抗抑郁作用，防止应激诱导的星形胶质细胞 Cx43 半通道活性和 vHipp 细胞外谷氨酸的增加，没有镇静或运动副作用。总之，慢性压力会增加 vHipp 中星形胶质细胞中谷氨酸和 D-/L-丝氨酸的 Cx43 半通道依赖性释放，过度激活突触后 NMDAR 并引发抑郁样症状。这项研究强调了星形胶质细胞胶质递质释放在慢性压力诱导的抑郁症中的关键作用，并表明它可以用作预防和治疗抑郁症的靶点。