Stimulation of Glia Reveals Modulation of Mammalian Spinal Motor Networks by Adenosine.
Stimulation of Glia Reveals Modulation of Mammalian Spinal Motor Networks by Adenosine.
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DOI：
10.1371/journal.pone.0134488
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Miles GB
中科院分区：
文献类型：
--
作者：
Acton D;Miles GB
尽管有大量证据表明神经胶质细胞可以释放调节剂来影响邻近神经元的兴奋性，但神经胶质细胞传输对于神经网络运行和塑造行为的重要性仍然存在争议。在这里，我们描述了神经胶质细胞对哺乳动物脊髓运动中枢模式发生器调节的贡献，其输出与定义的行为直接相关。蛋白酶激活受体 1 (PAR1) 的特异性激活刺激神经胶质细胞，PAR1 是一种内源性 G 蛋白偶联受体，在脊髓中枢模式发生器持续活动期间优先由脊髓神经胶质细胞表达。激动剂 TFLLR 选择性激活 PAR1 导致新生小鼠脊髓制剂腹根记录的运动相关爆发频率可逆性降低。在胶毒素甲硫氨酸亚砜亚胺或氟乙酸酯存在的情况下，TFLLR 没有作用，证实了 PAR1 激活对神经胶质细胞的特异性。 PAR1 激活时的爆发频率调节被非选择性腺苷受体拮抗剂茶碱和 A1 受体拮抗剂 8-环戊基-1,3-二丙基黄嘌呤阻断，但不被 A2A 受体拮抗剂 SCH5826 阻断，表明神经胶质刺激后细胞外腺苷产生，随后是 A1 受体介导的神经元活动抑制。神经胶质细胞刺激后的网络输出调节也被核酸外切酶抑制剂 ARL67156 阻断，表明神经胶质细胞释放 ATP 并随后降解为腺苷，而不是直接释放腺苷。神经胶质刺激对抑制性传导阻断后记录的节律活动没有影响，这表明神经胶质细胞来源的腺苷通过抑制回路成分发挥作用，调节运动相关的输出。最后，发现内源性腺苷对网络输出的调节与网络活动的频率成比例，这意味着腺苷的释放依赖于活动。总之，这些数据表明神经胶质细胞在哺乳动物运动网络的调节中发挥着积极作用，提供可以稳定网络活动的负反馈控制。
Despite considerable evidence that glia can release modulators to influence the excitability of neighbouring neurons, the importance of gliotransmission for the operation of neural networks and in shaping behaviour remains controversial. Here we characterise the contribution of glia to the modulation of the mammalian spinal central pattern generator for locomotion, the output of which is directly relatable to a defined behaviour. Glia were stimulated by specific activation of protease-activated receptor-1 (PAR1), an endogenous G-protein coupled receptor preferentially expressed by spinal glia during ongoing activity of the spinal central pattern generator for locomotion. Selective activation of PAR1 by the agonist TFLLR resulted in a reversible reduction in the frequency of locomotor-related bursting recorded from ventral roots of spinal cord preparations isolated from neonatal mice. In the presence of the gliotoxins methionine sulfoximine or fluoroacetate, TFLLR had no effect, confirming the specificity of PAR1 activation to glia. The modulation of burst frequency upon PAR1 activation was blocked by the non-selective adenosine-receptor antagonist theophylline and by the A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, but not by the A2A-receptor antagonist SCH5826, indicating production of extracellular adenosine upon glial stimulation, followed by A1-receptor mediated inhibition of neuronal activity. Modulation of network output following glial stimulation was also blocked by the ectonucleotidase inhibitor ARL67156, indicating glial release of ATP and its subsequent degradation to adenosine rather than direct release of adenosine. Glial stimulation had no effect on rhythmic activity recorded following blockade of inhibitory transmission, suggesting that glial cell-derived adenosine acts via inhibitory circuit components to modulate locomotor-related output. Finally, the modulation of network output by endogenous adenosine was found to scale with the frequency of network activity, implying activity-dependent release of adenosine. Together, these data indicate that glia play an active role in the modulation of mammalian locomotor networks, providing negative feedback control that may stabilise network activity.