Mice Deficient in lysophosphatidic acid acyltransferase delta (Lpaatδ)/acylglycerophosphate acyltransferase 4 (Agpat4) Have Impaired Learning and Memory

ABSTRACT

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 Lpaatδ^−/− 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 Lpaatδ^−/− mice was unchanged. Importantly, we found that Lpaatδ^−/− 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 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 Lpaatδ deficiency causes deficits in learning and memory associated with reduced NMDA and AMPA receptors.

KEYWORDS:

• AMPA receptors
• brain lipid metabolism
• enzymes
• glycerophosphatidylinositols
• learning
• memory
• mitochondrial metabolism
• NMDA receptors
• phospholipids

ACKNOWLEDGMENTS

We thank Erika Lui and Elham Satvat for technical assistance with MWM. We also thank Angela Wagler and Jean Flanagan for expert assistance in animal care. We acknowledge John Mielke for helpful discussions on learning and memory in mice.

This work was supported by grants to R.E.D. from the Canada Foundation for Innovation-Leader's Opportunity Fund and Ontario Research Fund (project 30259) and a Discovery Grant (418213-2012) and a Research Tools and Instruments Grant (EQPEQ-2015-472393) from the Natural Sciences and Engineering Research Council (NSERC) of Canada. E.B.M. is the recipient of an NSERC Master's Scholarship (PGS-M). R.M.B., D.B., J.J.A.H., A.S.M., and P.M.M. are the recipients of NSERC Doctoral Scholarships (PGS-D). D.B. was the recipient of an Ontario Graduate Scholarship (OGS).