Shao Li-Rong, Stafstrom Carl E
Division of Pediatric Neurology, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Division of Pediatric Neurology, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
J Neurophysiol. 2017 Jul 1;118(1):103-113. doi: 10.1152/jn.00100.2017. Epub 2017 Apr 12.
Neuronal activity is energy demanding and coupled to cellular metabolism. In this study, we investigated the effects of glycolytic inhibition with 2-deoxy-d-glucose (2-DG) on basal membrane properties, spontaneous neuronal firing, and epileptiform network bursts in hippocampal slices. The effect of glycolytic inhibition on basal membrane properties was examined in hippocampal CA1 neurons, which are not ordinarily active spontaneously. Intracellular application of 2-DG did not significantly alter the membrane input resistance, action-potential threshold, firing pattern, or input-output relationship of these neurons compared with simultaneously recorded neighboring neurons without intracellular 2-DG. The effect of glycolytic inhibition on neuronal firing was tested in spontaneously active hippocampal neurons (CA3) when synaptic transmission was left intact or blocked with AMPA, NMDA, and GABA receptor antagonists (DNQX, APV, and bicuculline, respectively). Under both conditions (synaptic activity intact or blocked), bath application of 2-DG (2 mM) blocked spontaneous firing in ~2/3 (67 and 71%, respectively) of CA3 pyramidal neurons. In contrast, neuronal firing of CA3 neurons persisted when 2-DG was applied intracellularly, suggesting that glycolytic inhibition of individual neurons is not sufficient to stop neuronal firing. The effects of 2-DG on epileptiform network bursts in area CA3 were tested in Mg-free medium containing 50 µM 4-aminopyridine. Bath application of 2-DG abolished these epileptiform bursts in a dose-dependent and all-or-none manner. Taken together, these data suggest that altered glucose metabolism profoundly affects cellular and network hyperexcitability and that glycolytic inhibition by 2-DG can effectively abrogate epileptiform activity. Neuronal activity is highly energy demanding and coupled to cellular metabolism. In this study, we demonstrate that glycolytic inhibition with 2-deoxy-d-glucose (2-DG) effectively suppresses spontaneous neuronal firing and epileptiform bursts in hippocampal slices. These data suggest that an altered metabolic state can profoundly affect cellular and network excitability, and that the glycolytic inhibitor 2-DG may hold promise as a novel treatment of drug-resistant epilepsy.
神经元活动需要能量，并与细胞代谢相关联。在本研究中，我们研究了用2-脱氧-D-葡萄糖（2-DG）抑制糖酵解对海马切片中基础膜特性、神经元自发放电以及癫痫样网络爆发的影响。在通常不会自发活动的海马CA1神经元中检测了糖酵解抑制对基础膜特性的影响。与同时记录的未进行细胞内2-DG处理的相邻神经元相比，细胞内应用2-DG并未显著改变这些神经元的膜输入电阻、动作电位阈值、放电模式或输入-输出关系。当突触传递保持完整或用AMPA、NMDA和GABA受体拮抗剂（分别为DNQX、APV和荷包牡丹碱）阻断时，在自发活动的海马神经元（CA3）中测试了糖酵解抑制对神经元放电的影响。在这两种条件下（突触活动完整或阻断），浴槽应用2-DG（2 mM）可阻断约2/3的CA3锥体神经元的自发放电（分别为67%和71%）。相比之下，当细胞内应用2-DG时，CA3神经元的放电持续存在，这表明对单个神经元的糖酵解抑制不足以阻止神经元放电。在含有50 μM 4-氨基吡啶的无镁培养基中测试了2-DG对CA3区癫痫样网络爆发的影响。浴槽应用2-DG以剂量依赖性和全或无的方式消除了这些癫痫样爆发。综上所述，这些数据表明葡萄糖代谢改变会深刻影响细胞和网络的过度兴奋性，并且2-DG抑制糖酵解可有效消除癫痫样活动。神经元活动对能量需求极高，并与细胞代谢相关联。在本研究中，我们证明用2-脱氧-D-葡萄糖（2-DG）抑制糖酵解可有效抑制海马切片中的神经元自发放电和癫痫样爆发。这些数据表明代谢状态改变可深刻影响细胞和网络兴奋性，并且糖酵解抑制剂2-DG可能有望成为治疗耐药性癫痫的新方法。
