Mice Deficient inlysophosphatidic 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 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 thatδ deficiency causes deficits in learning and memory associated with reduced NMDA and AMPA receptors.

Messenger RNA levels of enzymes involved in glycerolipid synthesis in the brain of the mouse and its alterations in Agpat2-/- and db/db mice

“…AGPAT4 was previously reported as the most abundant AGPAT isoform in whole mouse brain preparations (32) and its mRNA was detectable at similar levels between brain stem, cerebellum, cortex, hippocampus and olfactory bulb in mice (33). Agpat4 −/− mice have impaired spatial learning and memory, in association with drastically decreased NMDA and AMPA receptor levels in the brain (34). On the other hand, AGPAT4 is involved in phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol synthesis in the brain (33); however, whether phospholipid alterations are connected to the neurological defects of the AGPAT4 de cient mice remains to be elucidated.…”

The Structure and Function of Acylglycerophosphate Acyltransferase 4/ Lysophosphatidic Acid Acyltransferase Delta (AGPAT4/LPAATδ)

“…Lysophosphatidic acid acyltransferase δ is most highly expressed in brain (Eto et al, 2014; Bradley et al, 2015, 2016, 2017), but also in muscle (Bradley and Duncan, 2018) and, to a lesser extent, in other tissues, such as lungs, intestines, epidermis, and spleen. At the level of the mouse central nervous system, LPAATδ is abundant at the brain stem, cortex, hippocampus, cerebellum and olfactory bulbs (Bradley et al, 2015).…”

“…Lpaatδ - mice have significant impairments in spatial learning and memory (Bradley et al, 2017). This phenomenon can be partly attributed to the drastically lower brain content of the NMDA receptor subunits (namely NR1, NR2A, and NR2B), and of the GluR1 subunit of the AMPA receptor.…”

“…This phenomenon can be partly attributed to the drastically lower brain content of the NMDA receptor subunits (namely NR1, NR2A, and NR2B), and of the GluR1 subunit of the AMPA receptor. NMDA receptor and AMPA receptor are two glutamate-gated transmembrane proteins involved in synaptic plasticity and memory (Bradley et al, 2017). Such a significantly reduced neural content of these subunits, in turn, might be explained by the noticeable decrease in PI, PE, and PC in the brain of Lpaatδ - mice.…”

“…Such a significantly reduced neural content of these subunits, in turn, might be explained by the noticeable decrease in PI, PE, and PC in the brain of Lpaatδ - mice. The presence of these glycerophospholipids might be required to preserve the biophysical properties of neuronal membranes in order to generate the conditions for the correct assembly and function of these receptors (Bradley et al, 2017). Specific lipids have been reported to have a modulatory role in the structure and function of many membrane proteins (Opekarova and Tanner, 2003; Lee, 2004; Bogdanov et al, 2008; Zhukovsky et al, 2013; and references therein).…”