AGPAT4 is a Mitochondrial Lysophosphatidic Acid Acyltransferase that Regulates Learning and Memory in Mice

Abstract

We have previously characterized acylglycerophosphate acyltransferase 4 (AGPAT4) as a mitochondrial lysophosphatidic acid acyltransferase. We have also determined that AGPAT4 is important in the regulation of brain levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI), since levels of these glycerophospholipids were decreased significantly by 38%, 32%, and 52%, respectively, in the brains of Agpat4−/− mice. We investigated whether there were any impairments in cognition that may occur due to the significant loss of these three major glycerophospholipid species in the brains of Agpat4−/− mice. We tested the behaviour of Agpat4−/− mice and found that they have impaired spatial learning and memory as compared to wildtype littermates when assessed using the Morris Water Maze (MWM). Mechanisms underlying this effect were studied. No differences in whole‐body physiological parameters including respiratory capacity, food intake, motion and activity, or respiratory exchange ratio were evident. Similarly, we did not detect any changes with loss of Agpat4 in the brain mitochondrial content, or in the function of mitochondrial complexes as assessed in isolated brain mitochondria using high‐resolution respirometry. And, finally, we found that downstream targets of polyphosphorylated PI‐mediated signaling were also unchanged. However, Agpat4−/− mice did have a significantly lower brain content of the NMDA receptor subunits NR2A and NR2B, as well as the AMPA receptor subunit GluR1. Our findings indicate that neuronal membrane phospholipid content and composition are important in regulating NMDA and AMPA receptor content with implications for learning and memory.Support or Funding InformationThis work was supported by grants to RED from the Canada Foundation for Innovation – Leader's Opportunity Fund and Ontario Research Fund (Project#30259), and a Discovery Grant (#418213‐2012) from the Natural Sciences and Engineering Research Council (NSERC) of Canada. EBM is the recipient of an NSERC Master's Scholarship (PGS‐M). RMB, JJAH, ASM, DB, PMM are the recipients of an NSERC Doctoral Scholarship (PGS‐D).