Astrocytic GABABReceptors in Mouse Hippocampus Control Responses to Behavioral Challenges through Astrocytic BDNF
Astrocytic GABABReceptors in Mouse Hippocampus Control Responses to Behavioral Challenges through Astrocytic BDNF
复制标题
小鼠海马星形胶质细胞 GABA(B) 受体通过星形胶质细胞 BDNF 控制对行为挑战的反应
DOI：
10.1007/s12264-020-00474-x
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发表时间：
2020-07-01
影响因子：
5.6
通讯作者：
Gao, Tian-Ming
中科院分区：
文献类型：
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作者：
Liu, Ji-Hong;Li, Ze-Lin;Gao, Tian-Ming
重度抑郁症（MDD）是一种常见的情绪障碍，影响全球近20%的人口。此外，许多证据表明抑郁症的病理生理学中γ-氨基丁酸（GABA能）系统的功能改变。最近的研究表明，GABA（B）受体（GABA（B）Rs）是治疗应激相关疾病如MDD的新兴治疗靶点。然而，GABA（B）受体参与这一过程的细胞类型是未知的。由于海马功能障碍与MDD有关，我们敲低海马中的GABA（B）受体，发现敲低星形胶质细胞中的这些受体，而不是GABA能或锥体神经元中的受体，导致强迫游泳试验（FST）中不动性的减少，而不影响其他焦虑和抑郁相关行为。我们还产生了星形胶质细胞特异性GABA（B）R基因敲除小鼠，发现这些小鼠的FST不动性降低。此外，条件性敲除星形胶质细胞中的GABA（B）Rs选择性地增加海马星形胶质细胞中脑源性神经营养因子蛋白的水平，这控制了FST中不动性的降低。总之，我们的研究结果有助于目前的理解，表达GABA（B）Rs的细胞类型调节FST的抗抑郁活性，他们可能会提供新的见解的病理机制和潜在的目标，为治疗抑郁症。
Major depressive disorder (MDD) is a common mood disorder that affects almost 20% of the global population. In addition, much evidence has implicated altered function of the gamma-aminobutyric acid (GABAergic) system in the pathophysiology of depression. Recent research has indicated that GABA(B)receptors (GABA(B)Rs) are an emerging therapeutic target in the treatment of stress-related disorders such as MDD. However, which cell types with GABA(B)Rs are involved in this process is unknown. As hippocampal dysfunction is implicated in MDD, we knocked down GABA(B)Rs in the hippocampus and found that knocking down these receptors in astrocytes, but not in GABAergic or pyramidal neurons, caused a decrease in immobility in the forced swimming test (FST) without affecting other anxiety- and depression-related behaviors. We also generated astrocyte-specific GABA(B)R-knockout mice and found decreased immobility in the FST in these mice. Furthermore, the conditional knockout of GABA(B)Rs in astrocytes selectively increased the levels of brain-derived neurotrophic factor protein in hippocampal astrocytes, which controlled the decrease in immobility in the FST. Taken together, our findings contribute to the current understanding of which cell types expressing GABA(B)Rs modulate antidepressant activity in the FST, and they may provide new insights into the pathological mechanisms and potential targets for the treatment of depression.