Clozapine induces astrocyte-dependent FDG-PET hypometabolism
Clozapine induces astrocyte-dependent FDG-PET hypometabolism
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氯氮平诱导星形胶质细胞依赖性 FDG-PET 代谢减退
DOI：
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发表时间：
2021
影响因子：
9.1
通讯作者：
E. Zimmer
中科院分区：
文献类型：
--
作者：
A. Rocha;B. Bellaver;D. G. Souza;G. Schu;I. Fontana;G. Venturin;S. Greggio;F. Fontella;M. L. Schiavenin;L. Machado;D. Miron;J. D. da Costa;P. Rosa;D. Souza;L. Pellerin;E. Zimmer
功能成像的进步使我们能够通过 [18F]氟-2-脱氧葡萄糖 (FDG) 正电子发射断层扫描 (PET) 成像以非侵入方式在体内可视化脑葡萄糖代谢。在过去的几十年中，FDG-PET 在了解健康和疾病中的大脑功能方面发挥了重要作用。 FDG-PET 信号的来源归因于神经元摄取，代谢低下被认为是神经元功能障碍或死亡的直接指标。然而，其他脑细胞也具有代谢活性，包括星形胶质细胞。根据星形胶质细胞-神经元乳酸穿梭假说，谷氨酸转运蛋白 1 (GLT-1) 的激活可触发星形胶质细胞摄取葡萄糖。考虑到这一点，我们研究了用抗精神病药物氯氮平 (CLO) 药理下调 GLT-1 后葡萄糖利用率的变化。成年雄性 Wistar 大鼠（对照，n = 14；CLO，n = 12）接受 CLO (25/35 mg kg−1) 6 周。使用 FDG-PET 评估体内 CLO 效应，并使用皮质组织评估谷氨酸摄取以及 GLT-1 和 GLAST 水平。还在皮质星形胶质细胞培养物（葡萄糖和谷氨酸摄取、GLT-1 和 GLAST 水平）和皮质神经元培养物（葡萄糖摄取）中评估了 CLO 治疗效果。 CLO 显着降低体内多个大脑区域的葡萄糖代谢，尤其是皮质。离体分析表明皮质谷氨酸转运减少以及 GLT-1 mRNA 和蛋白质下调。在星形胶质细胞培养物中，CLO 降低了 GLT-1 密度以及谷氨酸和葡萄糖的摄取。相比之下，在皮质神经元培养物中，CLO 并不影响葡萄糖的摄取。这项工作提供了体内证据，表明 GLT-1 下调会诱导星形胶质细胞依赖性皮质 FDG-PET 代谢低下（模仿痴呆症患者中观察到的低代谢特征），并进一步证明星形胶质细胞是 FDG-PET 信号的关键贡献者。
Advances in functional imaging allowed us to visualize brain glucose metabolism in vivo and non-invasively with [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) imaging. In the past decades, FDG-PET has been instrumental in the understanding of brain function in health and disease. The source of the FDG-PET signal has been attributed to neuronal uptake, with hypometabolism being considered as a direct index of neuronal dysfunction or death. However, other brain cells are also metabolically active, including astrocytes. Based on the astrocyte-neuron lactate shuttle hypothesis, the activation of the glutamate transporter 1 (GLT-1) acts as a trigger for glucose uptake by astrocytes. With this in mind, we investigated glucose utilization changes after pharmacologically downregulating GLT-1 with clozapine (CLO), an anti-psychotic drug. Adult male Wistar rats (control, n = 14; CLO, n = 12) received CLO (25/35 mg kg−1) for 6 weeks. CLO effects were evaluated in vivo with FDG-PET and cortical tissue was used to evaluate glutamate uptake and GLT-1 and GLAST levels. CLO treatment effects were also assessed in cortical astrocyte cultures (glucose and glutamate uptake, GLT-1 and GLAST levels) and in cortical neuronal cultures (glucose uptake). CLO markedly reduced in vivo brain glucose metabolism in several brain areas, especially in the cortex. Ex vivo analyses demonstrated decreased cortical glutamate transport along with GLT-1 mRNA and protein downregulation. In astrocyte cultures, CLO decreased GLT-1 density as well as glutamate and glucose uptake. By contrast, in cortical neuronal cultures, CLO did not affect glucose uptake. This work provides in vivo demonstration that GLT-1 downregulation induces astrocyte-dependent cortical FDG-PET hypometabolism—mimicking the hypometabolic signature seen in people developing dementia—and adds further evidence that astrocytes are key contributors of the FDG-PET signal.
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影响因子：
64.5
作者：
García-Cáceres C;Quarta C;Varela L;Gao Y;Gruber T;Legutko B;Jastroch M;Johansson P;Ninkovic J;Yi CX;Le Thuc O;Szigeti-Buck K;Cai W;Meyer CW;Pfluger PT;Fernandez AM;Luquet S;Woods SC;Torres-Alemán I;Kahn CR;Götz M;Horvath TL;Tschöp MH
通讯作者：
Tschöp MH
影响因子：
3.7
作者：
Jakoby, Patrick;Schmidt, Elke;Deitmer, Joachim W.
通讯作者：
Deitmer, Joachim W.
影响因子：
2.6
作者：
Berti, Valentina;Mosconi, Lisa;Pupi, Alberto
通讯作者：
Pupi, Alberto
DOI：
10.1098/rstb.1999.0472
发表时间：
1999-07-29
影响因子：
6.3
作者：
Rothman, DL;Sibson, NR;Shulman, RG
通讯作者：
Shulman, RG
DOI：
10.1073/pnas.95.1.316
发表时间：
1998-01-06
影响因子：
11.1
作者：
Sibson, NR;Dhankhar, A;Shulman, RG
通讯作者：
Shulman, RG