Liu Bei, Niu Le, Shen Ming-Zhi, Gao Lei, Wang Chao, Li Jie, Song Li-Jia, Tao Ye, Meng Qiang, Yang Qian-Li, Gao Guo-Dong, Zhang Hua
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, People's Republic of China.
Mol Neurobiol. 2014 Oct;50(2):327-38. doi: 10.1007/s12035-013-8619-z. Epub 2014 Jan 25.
Efflux of monocaroxylates like lactate, pyruvate, and ketone bodies from astrocytes through monocarboxylate transporter 4 (MCT4) supplies the local neuron population with metabolic intermediates to meet energy requirements under conditions of increased demand. Disruption of this astroglial-neuron metabolic coupling pathway may contribute to epileptogenesis. We measured MCT4 expression in temporal lobe epileptic foci excised from patients with intractable epilepsy and in rats injected with pilocarpine, an animal model of temporal lobe epilepsy (TLE). Cortical MCT4 expression levels were significantly lower in TLE patients compared with controls, due at least partially to MCT4 promoter methylation. Expression of MCT4 also decreased progressively in pilocarpine-treated rats from 12 h to 14 days post-administration. Underexpression of MCT4 in cultured astrocytes induced by a short hairpin RNA promoted apoptosis. Knockdown of astrocyte MCT4 also suppressed excitatory amino acid transporter 1 (EAAT1) expression. Reduced MCT4 and EAAT1 expression by astrocytes may lead to neuronal hyperexcitability and epileptogenesis in the temporal lobe by reducing the supply of metabolic intermediates and by allowing accumulation of extracellular glutamate.
像乳酸、丙酮酸和酮体这样的单羧酸通过单羧酸转运体4（MCT4）从星形胶质细胞外流，为局部神经元群体提供代谢中间体，以满足需求增加情况下的能量需求。这种星形胶质细胞 - 神经元代谢偶联途径的破坏可能有助于癫痫发生。我们测量了从难治性癫痫患者切除的颞叶癫痫病灶以及注射匹罗卡品（一种颞叶癫痫（TLE）动物模型）的大鼠中MCT4的表达。与对照组相比，TLE患者的皮质MCT4表达水平显著降低，至少部分原因是MCT4启动子甲基化。在匹罗卡品处理的大鼠中，从给药后12小时到14天，MCT4的表达也逐渐降低。短发夹RNA诱导的培养星形胶质细胞中MCT4表达不足促进了细胞凋亡。星形胶质细胞MCT4的敲低也抑制了兴奋性氨基酸转运体1（EAAT1）的表达。星形胶质细胞中MCT4和EAAT1表达的降低可能通过减少代谢中间体的供应以及允许细胞外谷氨酸积累，导致颞叶神经元兴奋性过高和癫痫发生。
