Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
Transl Psychiatry. 2018 Apr 12;8(1):76. doi: 10.1038/s41398-018-0123-9.
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.
我们对于遗传风险变异如何导致精神疾病的认识主要局限于神经元。然而，同样的遗传风险因素影响神经胶质细胞生理学的机制仍知之甚少。我们研究了一种精神疾病遗传风险因子——精神分裂症相关蛋白 1（DISC1）在星形胶质细胞代谢功能中的作用。我们评估了敲低小鼠内源性 DISC1（DISC1-KD）和表达显性负性、截断 C 端的人 DISC1（DN-DISC1）对能量代谢标志物的影响，包括原代星形胶质细胞中的葡萄糖摄取和乳酸生成，以及在星形胶质细胞中选择性表达 DN-DISC1 的小鼠中。我们还评估了乳酸处理对改变的情感行为和 DN-DISC1 小鼠空间记忆受损的影响。DISC1-KD 和 DN-DISC1 均可降低原代星形胶质细胞葡萄糖转运蛋白 4 的 mRNA 和蛋白水平以及葡萄糖摄取。葡萄糖摄取减少与体外和体内氧化磷酸化和糖酵解减少以及乳酸生成减少有关。在星形胶质细胞中，DISC1 操作对电子传递链复合物亚基或神经元 DISC1 伴侣 mitofilin 的表达没有明显影响。乳酸处理可挽救 DN-DISC1 雄性和雌性小鼠的异常行为。我们的结果表明，DISC1 可能参与调节星形胶质细胞中乳酸的产生，以支持神经元活动和相关行为。星形胶质细胞中 DISC1 的异常表达和由此产生的能量供应异常可能是导致重大精神疾病患者出现情绪和认知障碍的部分原因。
