Pallud Johan, Le Van Quyen Michel, Bielle Franck, Pellegrino Christophe, Varlet Pascale, Cresto Noemie, Baulac Michel, Duyckaerts Charles, Kourdougli Nazim, Chazal Geneviève, Devaux Bertrand, Rivera Claudio, Miles Richard, Capelle Laurent, Huberfeld Gilles
Institut du Cerveau et de la Moelle Epinière, INSERM UMRS975, CNRS UMR7225, Université Pierre et Marie Curie (UPMC), Paris, France.
Service de Neurochirurgie, Centre Hospitalier Sainte-Anne, Paris, France.
Sci Transl Med. 2014 Jul 9;6(244):244ra89. doi: 10.1126/scitranslmed.3008065.
Brain gliomas are highly epileptogenic. Excitatory glutamatergic mechanisms are involved in the generation of epileptic activities in the neocortex surrounding gliomas. However, chloride homeostasis is known to be perturbed in glioma cells. Thus, the contribution of γ-aminobutyric acidergic (GABAergic) mechanisms that depend on intracellular chloride merits closer study. We studied the occurrence, networks, cells, and signaling basis of epileptic activities in neocortical slices from the peritumoral surgical margin resected around human brain gliomas. Postoperative glioma tissue from 69% of patients spontaneously generated interictal-like discharges, synchronized, with a high-frequency oscillation signature, in superficial layers of neocortex around areas of glioma infiltration. Interictal-like events depended both on glutamatergic AMPA receptor-mediated transmission and on depolarizing GABAergic signaling. GABA released by interneurons depolarized 65% of pyramidal cells, in which chloride homeostasis was perturbed because of changes in expression of neuronal chloride cotransporters: KCC2 (K-Cl cotransporter 2) was reduced by 42% and expression of NKCC1 (Na-K-2Cl cotransporter 1) increased by 144%. Ictal-like activities were initiated by convulsant stimuli exclusively in these epileptogenic areas. This study shows that epileptic activities are sustained by excitatory effects of GABA in human peritumoral neocortex, as reported in temporal lobe epilepsies, suggesting that both glutamate and GABA signaling and cellular chloride regulation processes, all also involved in oncogenesis as already shown, induce an imbalance between synaptic excitation and inhibition underlying epileptic discharges in glioma patients. Thus, the control of chloride in neurons and glioma cells may provide a therapeutic target for patients with epileptogenic gliomas.
脑胶质瘤具有高度致痫性。兴奋性谷氨酸能机制参与了胶质瘤周围新皮层癫痫活动的产生。然而，已知胶质瘤细胞中的氯离子稳态受到干扰。因此，依赖细胞内氯离子的γ-氨基丁酸能（GABA能）机制的作用值得更深入研究。我们研究了从人脑胶质瘤周围切除的瘤周手术切缘的新皮层切片中癫痫活动的发生、网络、细胞及信号基础。69%的患者术后胶质瘤组织在胶质瘤浸润区域周围的新皮层浅层自发产生类发作间期放电，呈同步化且具有高频振荡特征。类发作间期事件既依赖于谷氨酸能AMPA受体介导的传递，也依赖于去极化GABA能信号传导。中间神经元释放的GABA使65%的锥体细胞去极化，由于神经元氯同向转运体表达的变化，这些细胞中的氯离子稳态受到干扰：钾氯共转运体2（KCC2）减少了42%，钠钾氯共转运体1（NKCC1）的表达增加了144%。类发作期活动仅在这些致痫区域由惊厥刺激引发。这项研究表明，如在颞叶癫痫中所报道的那样，癫痫活动在人类瘤周新皮层中由GABA的兴奋作用维持，这表明谷氨酸和GABA信号传导以及细胞氯调节过程，如已表明的那样也参与肿瘤发生，在胶质瘤患者中诱发了癫痫放电背后的突触兴奋与抑制之间的失衡。因此，控制神经元和胶质瘤细胞中的氯离子可能为致痫性胶质瘤患者提供一个治疗靶点。
