Astrocytic control of extra-cellular GABA drives circadian time-keeping in the suprachiasmatic nucleus
Astrocytic control of extra-cellular GABA drives circadian time-keeping in the suprachiasmatic nucleus
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星形胶质细胞对细胞外 GABA 的控制驱动视交叉上核的昼夜节律计时
DOI：
10.1101/2023.01.16.523253
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Patton A
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文献类型：
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作者：
Patton A
下丘脑视交叉上核（SCN）是哺乳动物的生物钟。它的细胞自主计时机制，转录/翻译反馈环（TTFL），驱动神经元电活动的每日峰值，这反过来又控制昼夜节律行为。由神经肽介导的细胞间信号同步并放大TTFL和电路中的电节律。SCN神经元是GABA能的，但GABA在回路水平计时中的作用尚不清楚。GABA能回路如何维持电活动的昼夜周期，而这种增加的神经元放电应该成为网络的抑制？为了探索这一矛盾，我们表明，SCN切片表达GABA传感器iGABASnFR表现出昼夜节律振荡的细胞外GABA（[GABA]e），违反直觉，运行在反相的神经元活动，在昼夜节律的夜晚和明显的低谷在昼夜节律的日子。解决这个意想不到的关系，我们发现，[GABA]eis调节GABA转运蛋白（GATs），与摄取峰值在昼夜节律的一天，因此白天低谷和夜间高峰。这种摄取是由星形胶质细胞表达的转运蛋白GAT 3（Slc 6a 11）介导的，其表达受昼夜节律调节，在白天升高。昼夜节律中[GABA]的清除促进神经元放电，并且对于神经肽血管活性肠肽的昼夜节律释放是必需的，血管活性肠肽是TTFL和回路水平节律的关键调节剂。最后，我们表明，单独的星形胶质细胞TTFL的遗传互补，否则无时钟SCN，足以驱动[GABA]节律和控制网络的计时。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昼夜节律时钟。
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]eis 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]ein 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]erhythms and control network timekeeping. Thus, astrocytic clocks maintain the SCN circadian clockwork by temporally controlling GABAergic inhibition of SCN neurons.