Electrical and synaptic integration of glioma into neural circuits
Electrical and synaptic integration of glioma into neural circuits
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DOI：
10.1038/s41586-019-1563-y
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发表时间：
2019-09-26
期刊：
影响因子：
64.8
通讯作者：
Monje, Michelle
中科院分区：
文献类型：
--
作者：
Venkatesh, Humsa S.;Morishita, Wade;Monje, Michelle
高级别神经胶质瘤是致命的脑癌，其进展受到神经元活动的强烈调控。活性调节的生长因子释放促进胶质瘤生长，但这本身不足以解释神经元活性对胶质瘤进展的影响。在这里，我们表明，神经元和胶质瘤的相互作用，包括通过真正的AMPA受体依赖的神经元-胶质瘤突触的电化学通信。神经元活动还引起非突触活动依赖性钾电流，该钾电流通过间隙连接介导的肿瘤互连而放大，形成电耦合网络。通过体内光遗传学评估的胶质瘤膜的去极化促进增殖，而阻断或遗传阻断电化学信号传导抑制胶质瘤异种移植物的生长并延长小鼠存活。强调神经胶质瘤增加神经元兴奋性的正反馈机制，从而活性调节神经胶质瘤的生长，人术中皮质电描记术表明神经胶质瘤浸润的大脑皮质兴奋性增加。总之，这些发现表明突触和电整合到神经回路中促进胶质瘤进展。
High-grade gliomas are lethal brain cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors promotes glioma growth, but this alone is insufficient to explain the effect that neuronal activity exerts on glioma progression. Here we show that neuron and glioma interactions include electrochemical communication through bona fide AMPA receptor-dependent neuron-glioma synapses. Neuronal activity also evokes non-synaptic activity-dependent potassium currents that are amplified by gap junction-mediated tumour interconnections, forming an electrically coupled network. Depolarization of glioma membranes assessed by in vivo optogenetics promotes proliferation, whereas pharmacologically or genetically blocking electrochemical signalling inhibits the growth of glioma xenografts and extends mouse survival. Emphasizing the positive feedback mechanisms by which gliomas increase neuronal excitability and thus activity-regulated glioma growth, human intraoperative electrocorticography demonstrates increased cortical excitability in the glioma-infiltrated brain. Together, these findings indicate that synaptic and electrical integration into neural circuits promotes glioma progression.