GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor-associated epilepsy.
GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor-associated epilepsy.
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DOI：
10.1002/glia.22730
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发表时间：
2015-01
期刊：
影响因子：
6.2
通讯作者：
Sontheimer, Harald
中科院分区：
文献类型：
--
作者：
Campbell, Susan L.;Robel, Stefanie;Cuddapah, Vishnu A.;Robert, Stephanie;Buckingham, Susan C.;Kahle, Kristopher T.;Sontheimer, Harald
神经胶质瘤常伴有癫痫发作，并常升级为瘤周癫痫。先前的研究揭示了由胱氨酸-谷氨酸转运体（SXC）介导的肿瘤源性兴奋性谷氨酸（Glu）释放在癫痫发生中的重要性。我们现在展示了gaba能解除抑制对疾病病理生理的新贡献。在一个经过验证的小鼠胶质瘤模型中，我们发现瘤周细小蛋白阳性的gaba能抑制性中间神经元显著减少，与自发和诱发抑制性神经传递的缺陷相对应。大多数剩余的肿瘤周围神经元表现出细胞内Cl−浓度升高（[Cl−]i），从而产生去极化、兴奋性GABA反应。在这些神经元中，KCC2的质浆表达显著降低，而KCC2是gabaar介导的抑制所需的低[Cl−]i。有趣的是，抑制降低与Glu释放无关，但抑制降低和SXC表达降低是癫痫发生所必需的。我们认为，gaba能解除抑制使肿瘤周围神经网络高度兴奋，易受兴奋性刺激引发的癫痫发作的影响，并提出KCC2作为治疗靶点。
Seizures frequently accompany gliomas and often escalate to peritumoral epilepsy. Previous work revealed the importance of tumor-derived excitatory glutamate (Glu) release mediated by the cystine-glutamate transporter (SXC) in epileptogenesis. We now show a novel contribution of GABAergic disinhibition to disease pathophysiology. In a validated mouse glioma model, we found that peritumoral parvalbumin-positive GABAergic inhibitory interneurons are significantly reduced, corresponding with deficits in spontaneous and evoked inhibitory neurotransmission. Most remaining peritumoral neurons exhibit elevated intracellular Cl− concentration ([Cl−]i) and consequently depolarizing, excitatory GABA responses. In these neurons, the plasmalemmal expression of KCC2, which establishes the low [Cl−]i required for GABAAR-mediated inhibition, is significantly decreased. Interestingly, reductions in inhibition are independent of Glu release, but the presence of both decreased inhibition and decreased SXC expression is required for epileptogenesis. We suggest GABAergic disinhibition renders peritumoral neuronal networks hyper-excitable and susceptible to seizures triggered by excitatory stimuli, and propose KCC2 as a therapeutic target.
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