DISC1 regulates lactate metabolism in astrocytes: implications for psychiatric disorders.
DISC1 regulates lactate metabolism in astrocytes: implications for psychiatric disorders.
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DOI：
10.1038/s41398-018-0123-9
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发表时间：
2018-04-12
影响因子：
6.8
通讯作者：
Pletnikov MV
中科院分区：
文献类型：
--
作者：
Jouroukhin Y;Kageyama Y;Misheneva V;Shevelkin A;Andrabi S;Prandovszky E;Yolken RH;Dawson VL;Dawson TM;Aja S;Sesaki H;Pletnikov MV
我们对遗传风险变异如何导致精神疾病的了解主要仅限于神经元。然而，相同的遗传风险因素影响神经胶质细胞生理学的机制仍然知之甚少。我们研究了精神遗传危险因素 Disrupted-In-Schizophrenia-1 (DISC1) 在星形胶质细胞代谢功能中的作用。我们评估了小鼠内源性 DISC1 (DISC1-KD) 敲低和显性失活、C 端截短的人 DISC1 (DN-DISC1) 表达对原代星形胶质细胞和星形胶质细胞中选择性表达 DN-DISC1 的小鼠能量代谢标志物（包括葡萄糖摄取和乳酸生成）的影响。我们还评估了乳酸治疗对 DN-DISC1 小鼠情感行为改变和空间记忆受损的影响。 DISC1-KD 和 DN-DISC1 均显着降低葡萄糖转运蛋白 4 的 mRNA 和蛋白质水平以及原代星形胶质细胞的葡萄糖摄取。葡萄糖摄取的减少与氧化磷酸化和糖酵解的减少以及体外和体内乳酸产生的减少有关。在星形胶质细胞中，未观察到 DISC1 操作对电子传递链复合物或神经元 DISC1 伴侣丝裂蛋白 (mitofilin) 亚基表达的显着影响。乳酸治疗挽救了 DN-DISC1 雄性和雌性小鼠的异常行为。我们的结果表明 DISC1 可能参与星形胶质细胞乳酸生成的调节，以支持神经元活动和相关行为。星形胶质细胞中 DISC1 的异常表达以及由此导致的能量供应异常可能是在患有重大精神疾病的患者中观察到的情绪和认知障碍的原因。
Our knowledge of how genetic risk variants contribute to psychiatric disease is mainly limited to neurons. However, the mechanisms whereby the same genetic risk factors could affect the physiology of glial cells remain poorly understood. We studied the role of a psychiatric genetic risk factor, Disrupted-In-Schizophrenia-1 (DISC1), in metabolic functions of astrocytes. We evaluated the effects of knockdown of mouse endogenous DISC1 (DISC1-KD) and expression of a dominant-negative, C-terminus truncated human DISC1 (DN-DISC1) on the markers of energy metabolism, including glucose uptake and lactate production, in primary astrocytes and in mice with selective expression of DN-DISC1 in astrocytes. We also assessed the effects of lactate treatment on altered affective behaviors and impaired spatial memory in DN-DISC1 mice. Both DISC1-KD and DN-DISC1 comparably decreased mRNA and protein levels of glucose transporter 4 and glucose uptake by primary astrocytes. Decreased glucose uptake was associated with reduced oxidative phosphorylation and glycolysis as well as diminished lactate production in vitro and in vivo. No significant effects of DISC1 manipulations in astrocytes were observed on expression of the subunits of the electron transport chain complexes or mitofilin, a neuronal DISC1 partner. Lactate treatment rescued the abnormal behaviors in DN-DISC1 male and female mice. Our results suggest that DISC1 may be involved in the regulation of lactate production in astrocytes to support neuronal activity and associated behaviors. Abnormal expression of DISC1 in astrocytes and resulting abnormalities in energy supply may be responsible for aspects of mood and cognitive disorders observed in patients with major psychiatric illnesses.
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