Astrocytic control of extracellular GABA drives circadian timekeeping in the suprachiasmatic nucleus.
Astrocytic control of extracellular GABA drives circadian timekeeping in the suprachiasmatic nucleus.
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DOI：
10.1073/pnas.2301330120
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发表时间：
2023-05-23
影响因子：
11.1
通讯作者：
Hastings MH
中科院分区：
文献类型：
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作者：
Patton AP;Morris EL;McManus D;Wang H;Li Y;Chin JW;Hastings MH
生物钟驱动着每天的生理节律，使我们适应白天和黑夜。由于社会压力（轮班工作）或疾病（神经退行性疾病）造成的破坏会带来严重的经济和健康后果。视交叉上核（SCN）是主要的大脑时钟，协调整个身体的节奏。它由使用抑制性神经递质GABA的相互连接的神经元和星形胶质细胞支持细胞组成。通过显微成像、药理学和分子遗传学方法，我们发现星形胶质细胞通过控制GABA水平的日常节律来维持SCN的计时。它们在白天的减少，通过增强清除，为神经元活动提供了一个昼夜节律窗口。这解决了一个长期存在的悖论，即排他抑制网络如何维持神经元活动，并突出了星形胶质细胞到神经元信号在生物钟中的关键重要性。下丘脑视交叉上核（SCN）是哺乳动物的主生物钟。它的细胞自主定时机制，一个转录/翻译反馈回路（TTFL），驱动神经元电活动的每日峰值，进而控制昼夜节律行为。细胞间信号，由神经肽介导，同步和放大TTFL和电节律在整个电路。SCN神经元具有GABA能，但GABA在电路水平计时中的作用尚不清楚。当这种增加的神经元放电对神经网络具有抑制作用时，gaba能回路如何维持电活动的昼夜周期？为了探索这一悖论，我们发现，表达GABA传感器iGABASnFR的SCN片显示出细胞外GABA （[GABA]e）的昼夜振荡，与直觉相反，与神经元活动相反，在昼夜节律的夜间有一个延长的峰值，在昼夜节律的白天有一个明显的低谷。为了解决这一意想不到的关系，我们发现[GABA]e受GABA转运体（GATs）的调节，其摄取在昼夜节律期间达到峰值，因此有白天和夜间的高峰。这种摄取是由星形细胞表达的转运体GAT3 （Slc6a11）介导的，其表达受昼夜调节，在白天升高。[GABA]e在昼夜节律日的清除促进了神经元放电，并且是神经肽血管活性肠肽的昼夜节律释放所必需的，而肠道肽是TTFL和回路水平节律性的关键调节因子。最后，我们证明了星形细胞TTFL的遗传互补，在其他无时钟的SCN中，足以驱动[GABA]e节律和控制网络计时。因此，星形细胞时钟通过暂时控制SCN神经元的gaba能抑制来维持SCN生物钟。
Circadian clocks drive daily physiological rhythms that adapt us to day and night. Their disruption by societal pressures (shift-work) or disease (neurodegeneration) carries severe economic and health consequences. The suprachiasmatic nucleus (SCN) is the principal brain clock, coordinating rhythms across the body. It consists of interconnected neurons that use the inhibitory neurotransmitter GABA, alongside astrocyte supporting cells. Using microscopic imaging, pharmacology, and molecular genetic approaches, we show that astrocytes sustain SCN timekeeping by controlling a daily rhythm of GABA levels. Their reduction during the day, by enhanced clearance, provides a circadian window for neuronal activity. This resolves a long-standing paradox of how an exclusively inhibitory network sustains neuronal activity and highlights the critical importance of astrocyte-to-neuron signaling in the clock. The hypothalamic suprachiasmatic nucleus (SCN) is the master mammalian circadian clock. Its cell-autonomous timing mechanism, a transcriptional/translational feedback loop (TTFL), drives daily peaks of neuronal electrical activity, which in turn control circadian behavior. Intercellular signals, mediated by neuropeptides, synchronize and amplify TTFL and electrical rhythms across the circuit. SCN neurons are GABAergic, but the role of GABA in circuit-level timekeeping is unclear. How can a GABAergic circuit sustain circadian cycles of electrical activity, when such increased neuronal firing should become inhibitory to the network? To explore this paradox, we show that SCN slices expressing the GABA sensor iGABASnFR demonstrate a circadian oscillation of extracellular GABA ([GABA]e) that, counterintuitively, runs in antiphase to neuronal activity, with a prolonged peak in circadian night and a pronounced trough in circadian day. Resolving this unexpected relationship, we found that [GABA]e is regulated by GABA transporters (GATs), with uptake peaking during circadian day, hence the daytime trough and nighttime peak. This uptake is mediated by the astrocytically expressed transporter GAT3 (Slc6a11), expression of which is circadian-regulated, being elevated in daytime. Clearance of [GABA]e in circadian day facilitates neuronal firing and is necessary for circadian release of the neuropeptide vasoactive intestinal peptide, a critical regulator of TTFL and circuit-level rhythmicity. Finally, we show that genetic complementation of the astrocytic TTFL alone, in otherwise clockless SCN, is sufficient to drive [GABA]e rhythms and control network timekeeping. Thus, astrocytic clocks maintain the SCN circadian clockwork by temporally controlling GABAergic inhibition of SCN neurons.
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影响因子：
16.6
作者：
Barca-Mayo O;Pons-Espinal M;Follert P;Armirotti A;Berdondini L;De Pietri Tonelli D
通讯作者：
De Pietri Tonelli D
影响因子：
16.2
作者：
Jin L;Han Z;Platisa J;Wooltorton JR;Cohen LB;Pieribone VA
通讯作者：
Pieribone VA
影响因子：
3.4
作者：
Kim, DY;Choi, HJ;Kim, YI
通讯作者：
Kim, YI
DOI：
10.1073/pnas.1319820111
发表时间：
2014-07-01
影响因子：
11.1
作者：
Farajnia, Sahar;van Westering, Tirsa L. E.;Michel, Stephan
通讯作者：
Michel, Stephan
影响因子：
6.2
作者：
通讯作者：
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