Age-associated increase in anxiety-like behavior in Lpaatδ/Agpat4 knockout mice

Abstract

We have previously reported deficits in phospholipids and NMDA-receptors in brains of 2–3 month-old mice deficient in the mitochondrial enzyme lysophosphatidic acid acyltransferase delta (LPAATδ)/acylglycerophosphate acyltransferase 4 (AGPAT4), which were associated with deficits in learning and memory. An initial assessment suggested these mice may also be predisposed to an anxiogenic-like behavioral phenotype, but this was not fully evident in young mice. Since some animal and human studies report worsening anxiety from middle-to-older adulthood, we hypothesized that aging may reveal a significant anxiety-like phenotype in Lpaatδ-deficient mice. We analyzed anxiety-like behavior in 14- and 20-month old Lpaatδ deficient (Lpaatδ−/−) mice and their wildtype age-matched littermate controls. Fourteen month-old Lpaatδ-deficient mice had ∼3-fold greater rearing activity over 24-h than controls. Aging was associated with a significant decrease in rearing activity in Lpaatδ-deficient mice, but not in wildtype control mice. However, rearing activity remained 59% higher in Lpaatδ-deficient mice than controls at 20 months of age. Behavior of Lpaatδ-deficient mice in the open field test and elevated plus maze also suggested a more anxiogenic-like phenotype, although differences between the genotypes were statistically significant only at 20 months. Brain NMDA receptor subunits were not significantly different between different ages or genotypes, which differed from prior results in younger mice. An initial screen of genes related to behavior indicated lower brain expression in Lpaatδ-deficient mice of the serotonin metabolism genes 5htr1a and slc6a4. These studies have implications for understanding associations between LPAATδ/AGPAT4 gene variants and human anxiety.

Keywords

• AGPAT4/LPAATδ
• Brain phospholipids
• Anxiety
• Elevated plus maze
• Open field test
• NMDA receptors