Metabolic modulation of synaptic failure and thalamocortical hypersynchronization with preserved consciousness in Glut1 deficiency.
Metabolic modulation of synaptic failure and thalamocortical hypersynchronization with preserved consciousness in Glut1 deficiency.
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DOI：
10.1126/scitranslmed.abn2956
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发表时间：
2022-10-05
影响因子：
17.1
通讯作者：
Pascual, Juan M.
中科院分区：
文献类型：
--
作者：
Rajasekaran, Karthik;Ma, Qian;Good, Levi B.;Kathote, Gauri;Jakkamsetti, Vikram;Liu, Peiying;Avila, Adrian;Primeaux, Sharon;Alva, Julio Enciso;Markussen, Kia H.;Marin-Valencia, Isaac;Sirsi, Deepa;Hacker, Peter M. S.;Gentry, Matthew S.;Su, Jianzhong;Lu, Hanzhang;Pascual, Juan M.
患有 I 型葡萄糖转运蛋白缺乏症 (G1D) 的个体习惯性地经历与脑葡萄糖降低相关的营养反应性癫痫。然而，G1D 背景下血糖浓度与大脑兴奋性之间的机制关联仍有待阐明。 G1D 个体的脑电图（EEG）显示，尽管电图概括且平均振荡持续时间和周期性均匀，但营养时间依赖性癫痫发作振荡通常与保留的意志相关，这表明潜在的神经环路的便利性增加。非线性脑电图发作源定位分析和同步脑电图/功能磁共振成像汇聚在丘脑-感觉运动皮层作为一个潜在回路，18F-脱氧葡萄糖正电子发射断层扫描（18F-DG-PET）显示该回路中葡萄糖积累减少。这种模式反映在丘脑与纹状体 18F 信号比的降低上，可以帮助 PET 成像诊断该疾病，而缺乏明显的发作行为变化则对意识期间正常丘脑皮质活动的假设要求提出了挑战。在 G1D 小鼠中，18F-DG-PET 和质谱分析也显示脑葡萄糖和糖原减少，但保留了三羧酸循环中间体，表明没有整体能量代谢失败。在这些动物的脑切片中，皮质锥体神经元和丘脑中继神经元的突触抑制减少，并且代谢碳源减轻了神经元去抑制；强直阵挛性癫痫发作也可通过 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸 (AMPA) 受体抑制来抑制。这些结果表明 G1D 是一种丘脑皮质突触去抑制疾病，与葡萄糖依赖性神经元兴奋性增加相关，可能与糖原减少有关。与其他代谢缺陷的发现一起，抑制性神经元功能障碍正在成为一种可调节的过度兴奋机制。
Individuals with glucose transporter type I deficiency (G1D) habitually experience nutrient-responsive epilepsy associated with decreased brain glucose. However, the mechanistic association between blood glucose concentration and brain excitability in the context of G1D remains to be elucidated. Electroencephalography (EEG) in G1D individuals revealed nutrition time-dependent seizure oscillations often associated with preserved volition despite electrographic generalization and uniform average oscillation duration and periodicity, suggesting increased facilitation of an underlying neural loop circuit. Nonlinear EEG ictal source localization analysis and simultaneous EEG/functional magnetic resonance imaging converged on the thalamus-sensorimotor cortex as one potential circuit, and 18F-deoxyglucose positron emission tomography (18F-DG-PET) illustrated decreased glucose accumulation in this circuit. This pattern, reflected in a decreased thalamic to striatal 18F signal ratio, can aid with the PET imaging diagnosis of the disorder, whereas the absence of noticeable ictal behavioral changes challenges the postulated requirement for normal thalamocortical activity during consciousness. In G1D mice, 18F-DG-PET and mass spectrometry also revealed decreased brain glucose and glycogen, but preserved tricarboxylic acid cycle intermediates, indicating no overall energy metabolism failure. In brain slices from these animals, synaptic inhibition of cortical pyramidal neurons and thalamic relay neurons was decreased, and neuronal disinhibition was mitigated by metabolic sources of carbon; tonic-clonic seizures were also suppressed by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition. These results pose G1D as a thalamocortical synaptic disinhibition disease associated with increased glucose-dependent neuronal excitability, possibly in relation to reduced glycogen. Together with findings in other metabolic defects, inhibitory neuron dysfunction is emerging as a modulable mechanism of hyperexcitability.
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影响因子：
82.9
作者：
Cope, David W.;Di Giovanni, Giuseppe;Fyson, Sarah J.;Orban, Gergely;Errington, Adam C.;Lorincz, Magor L.;Gould, Timothy M.;Carter, David A.;Crunelli, Vincenzo
通讯作者：
Crunelli, Vincenzo
影响因子：
4.3
作者：
Allaman I;Bélanger M;Magistretti PJ
通讯作者：
Magistretti PJ
影响因子：
11.2
作者：
Akman, Cigdem I.;Engelstad, Kristin;De Vivo, Darryl C.
通讯作者：
De Vivo, Darryl C.
影响因子：
2.5
作者：
D'Antuono, M;Inaba, Y;Avoli, M
通讯作者：
Avoli, M
影响因子：
2.8
作者：
Bartolomei, Fabrice;Naccache, Lionel
通讯作者：
Naccache, Lionel