Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism.
Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism.
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DOI：
10.1038/ncomms15132
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发表时间：
2017-05-02
影响因子：
16.6
通讯作者：
Hardingham GE
中科院分区：
文献类型：
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作者：
Hasel P;Dando O;Jiwaji Z;Baxter P;Todd AC;Heron S;Márkus NM;McQueen J;Hampton DW;Torvell M;Tiwari SS;McKay S;Eraso-Pichot A;Zorzano A;Masgrau R;Galea E;Chandran S;Wyllie DJA;Simpson TI;Hardingham GE
神经元对星形细胞功能的影响尚不清楚。为了研究这一点，我们首先开发了一个系统，将来自密切相关物种的皮质神经元和星形胶质细胞结合起来，然后进行RNA-seq和计算机物种分离。这种方法揭示了神经元诱导的星形细胞基因表达的广泛程序，包括Notch信号，它驱动和维持星形细胞成熟和神经递质摄取功能，在人类发育中是保守的，并被神经退行性变破坏。另外，数百个星形细胞基因通过cAMP/ pka依赖性CREB激活机制受到突触活性的剧烈调节。这包括星形胶质细胞-神经元乳酸穿梭的主要星形胶质细胞成分的协调活动依赖上调，导致星形胶质细胞葡萄糖代谢依赖creb增加和乳酸输出增加。此外，由神经元或神经元活动诱导的星形细胞基因群在人类中都表现出年龄依赖性衰退。因此，神经元和神经元活动调节星形胶质细胞转录组，具有塑造星形胶质细胞-神经元代谢合作的潜力。神经元和神经元活动如何调节星形胶质细胞功能尚不清楚。Hasel等人鉴定出两大类星形细胞基因，它们分别受神经元接触和突触活动调控，在星形细胞功能中发挥着不同的作用；有趣的是，许多这些基因在神经退行性变中失调。
The influence that neurons exert on astrocytic function is poorly understood. To investigate this, we first developed a system combining cortical neurons and astrocytes from closely related species, followed by RNA-seq and in silico species separation. This approach uncovers a wide programme of neuron-induced astrocytic gene expression, involving Notch signalling, which drives and maintains astrocytic maturity and neurotransmitter uptake function, is conserved in human development, and is disrupted by neurodegeneration. Separately, hundreds of astrocytic genes are acutely regulated by synaptic activity via mechanisms involving cAMP/PKA-dependent CREB activation. This includes the coordinated activity-dependent upregulation of major astrocytic components of the astrocyte–neuron lactate shuttle, leading to a CREB-dependent increase in astrocytic glucose metabolism and elevated lactate export. Moreover, the groups of astrocytic genes induced by neurons or neuronal activity both show age-dependent decline in humans. Thus, neurons and neuronal activity regulate the astrocytic transcriptome with the potential to shape astrocyte–neuron metabolic cooperation. How neurons and neuronal activity regulate astrocyte functions is poorly understood. Hasel et al. identify two large groups of astrocytic genes that are regulated by neuronal contact and synaptic activity respectively, with distinct roles in astrocytic function; interestingly, many of these genes are dysregulated in neurodegeneration.