Astrocyte deletion of Bmal1 alters daily locomotor activity and cognitive functions via GABA signalling.
Astrocyte deletion of Bmal1 alters daily locomotor activity and cognitive functions via GABA signalling.
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DOI：
10.1038/ncomms14336
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发表时间：
2017-02-10
影响因子：
16.6
通讯作者：
De Pietri Tonelli D
中科院分区：
文献类型：
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作者：
Barca-Mayo O;Pons-Espinal M;Follert P;Armirotti A;Berdondini L;De Pietri Tonelli D
昼夜节律由中央起搏器视交叉上核 (SCN) 中的时钟神经元网络控制。核心时钟基因（例如 Bmal1）在 SCN 神经元和其他脑细胞（例如星形胶质细胞）中表达。然而，星形胶质细胞时钟基因在控制节律行为中的作用尚不清楚。在这里，我们发现 GLAST 阳性星形胶质细胞中 Bmal1 的消融会改变小鼠的昼夜节律运动行为和认知。具体来说，星形胶质细胞 Bmal1 的缺失通过 GABA 信号传导对神经元时钟产生影响。重要的是，GABAA 受体信号传导的药理学调节完全挽救了行为表型。我们的研究结果揭示了星形细胞 Bmal1 对于协调神经元时钟的关键作用，并提出了一种新的细胞靶点——星形胶质细胞，用于昼夜节律短暂或慢性扰动的神经药理学，其中星形细胞时钟基因的改变可能会导致认知等神经行为输出的损害。核心时钟基因，如 Bmal1，在星形胶质细胞中表达，但它们对计时系统的贡献尚不清楚。巴萨-梅奥等人。报告称，Glast+ 星形胶质细胞中 Bmal1 的缺失会通过 GABA 信号传导改变神经元时钟，导致小鼠昼夜节律运动行为异常和认知受损。
Circadian rhythms are controlled by a network of clock neurons in the central pacemaker, the suprachiasmatic nucleus (SCN). Core clock genes, such as Bmal1, are expressed in SCN neurons and in other brain cells, such as astrocytes. However, the role of astrocytic clock genes in controlling rhythmic behaviour is unknown. Here we show that ablation of Bmal1 in GLAST-positive astrocytes alters circadian locomotor behaviour and cognition in mice. Specifically, deletion of astrocytic Bmal1 has an impact on the neuronal clock through GABA signalling. Importantly, pharmacological modulation of GABAA-receptor signalling completely rescues the behavioural phenotypes. Our results reveal a crucial role of astrocytic Bmal1 for the coordination of neuronal clocks and propose a new cellular target, astrocytes, for neuropharmacology of transient or chronic perturbation of circadian rhythms, where alteration of astrocytic clock genes might contribute to the impairment of the neurobehavioural outputs such as cognition. Core clock genes, such as Bmal1, are expressed in astrocytes, but their contribution to the timekeeping system is unknown. Barca-Mayo et al. report that deletion of Bmal1 in Glast+ astrocytes alters the neuronal clock through GABA signalling, leading to abnormal circadian locomotor behaviour and impaired cognition in mice.