Bradley Ryan M, Mardian Emily B, Bloemberg Darin, Aristizabal Henao Juan J, Mitchell Andrew S, Marvyn Phillip M, Moes Katherine A, Stark Ken D, Quadrilatero Joe, Duncan Robin E
University of Waterloo, Department of Kinesiology, Faculty of Applied Health Sciences, Waterloo, Ontario, Canada.
University of Waterloo, Department of Kinesiology, Faculty of Applied Health Sciences, Waterloo, Ontario, Canada
Mol Cell Biol. 2017 Oct 27;37(22). doi: 10.1128/MCB.00245-17. Print 2017 Nov 15.
We previously characterized LPAATδ/AGPAT4 as a mitochondrial lysophosphatidic acid acyltransferase that regulates brain levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI). Here, we report that δ mice display impaired spatial learning and memory compared to wild-type littermates in the Morris water maze and our investigation of potential mechanisms associated with brain phospholipid changes. Marker protein immunoblotting suggested that the relative brain content of neurons, glia, and oligodendrocytes was unchanged. Relative abundance of the important brain fatty acid docosahexaenoic acid was also unchanged in phosphatidylserine, phosphatidylglycerol, and cardiolipin, in agreement with prior data on PC, PE and PI. In phosphatidic acid, it was increased. Specific decreases in ethanolamine-containing phospholipids were detected in mitochondrial lipids, but the function of brain mitochondria in δ mice was unchanged. Importantly, we found that δ mice have a significantly and drastically lower brain content of the -methyl-d-asparate (NMDA) receptor subunits NR1, NR2A, and NR2B, as well as the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1, compared to wild-type mice. However, general dysregulation of PI-mediated signaling is not likely responsible, since phospho-AKT and phospho-mTOR pathway regulation was unaffected. Our findings indicate that δ deficiency causes deficits in learning and memory associated with reduced NMDA and AMPA receptors.
我们之前将溶血磷脂酸酰基转移酶δ/LPAATδ（即1-酰基甘油-3-磷酸酰基转移酶4/AGPAT4）鉴定为一种线粒体溶血磷脂酸酰基转移酶，它可调节脑内磷脂酰胆碱（PC）、磷脂酰乙醇胺（PE）和磷脂酰肌醇（PI）的水平。在此，我们报告称，与野生型同窝小鼠相比，δ基因敲除小鼠在莫里斯水迷宫实验中表现出空间学习和记忆受损，并且我们对与脑磷脂变化相关的潜在机制进行了研究。标记蛋白免疫印迹表明，神经元、神经胶质细胞和少突胶质细胞的相对脑含量未发生变化。在磷脂酰丝氨酸、磷脂酰甘油和心磷脂中，重要的脑脂肪酸二十二碳六烯酸的相对丰度也未发生变化，这与之前关于PC、PE和PI的数据一致。在磷脂酸中，其含量增加。在线粒体脂质中检测到含乙醇胺磷脂的特异性减少，但δ基因敲除小鼠脑线粒体的功能未发生变化。重要的是，我们发现与野生型小鼠相比，δ基因敲除小鼠脑中N-甲基-D-天冬氨酸（NMDA）受体亚基NR1、NR2A和NR2B以及α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体亚基GluR1的含量显著且大幅降低。然而，PI介导的信号传导一般失调不太可能是原因，因为磷酸化AKT和磷酸化mTOR途径的调节未受影响。我们的研究结果表明，δ基因缺失会导致与NMDA和AMPA受体减少相关的学习和记忆缺陷。
