期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 37, 期 22, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00245-17
关键词
AMPA receptors; brain lipid metabolism; enzymes; glycerophosphatidylinositols; learning; memory; mitochondrial metabolism; NMDA receptors; phospholipids
资金
- Canada Foundation for Innovation-Leader's Opportunity Fund
- Ontario Research Fund [30259]
- Natural Sciences and Engineering Research Council (NSERC) of Canada [EQPEQ-2015-472393, 418213-2012]
- NSERC Master's Scholarship (PGS-M)
- NSERC Doctoral Scholarships (PGS-D)
- Ontario Graduate Scholarship (OGS)
We previously characterized LPAAT delta/AGPAT4 as a mitochondrial lysophosphatidic acid acyltransferase that regulates brain levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI). Here, we report that Lpaat delta(-/-) 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 Lpaat delta(-/-) mice was unchanged. Importantly, we found that Lpaat delta(-/-) mice have a significantly and drastically lower brain content of the N-methyl-D-asparate (NMDA) receptor subunits NR1, NR2A, and NR2B, as well as the alpha-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 Lpaat delta deficiency causes deficits in learning and memory associated with reduced NMDA and AMPA receptors.
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