Imaging decreased brain docosahexaenoic acid metabolism and signaling in iPLA2β (VIA)-deficient mice

Abstract

Ca2+-independent phospholipase A2β (iPLA2β) selectively hydrolyzes docosahexaenoic acid (DHA, 22:6n-3) in vitro from phospholipid. Mutations in the PLA2G6 gene encoding this enzyme occur in patients with idiopathic neurodegeneration plus brain iron accumulation and dystonia-parkinsonism without iron accumulation, whereas mice lacking PLA2G6 show neurological dysfunction and neuropathology after 13 months. We hypothesized that brain DHA metabolism and signaling would be reduced in 4-month-old iPLA2β-deficient mice without overt neuropathology. Saline or the cholinergic muscarinic M1,3,5 receptor agonist arecoline (30 mg/kg) was administered to unanesthetized iPLA2β−/−, iPLA2β+/−, and iPLA2β+/+ mice, and [1-14C]DHA was infused intravenously. DHA incorporation coefficients k∗ and rates Jin, representing DHA metabolism, were determined using quantitative autoradiography in 81 brain regions. iPLA2β−/− or iPLA2β+/− compared with iPLA2β+/+ mice showed widespread and significant baseline reductions in k∗ and Jin for DHA. Arecoline increased both parameters in brain regions of iPLA2β+/+ mice but quantitatively less so in iPLA2β−/− and iPLA2β+/− mice. Consistent with iPLA2β’s reported ability to selectively hydrolyze DHA from phospholipid in vitro, iPLA2β deficiency reduces brain DHA metabolism and signaling in vivo at baseline and following M1,3,5 receptor activation. Positron emission tomography might be used to image disturbed brain DHA metabolism in patients with PLA2G6 mutations.

Keywords

• Ca2+-independent phospholipase A2
• iPLA2 knockout mouse
• brain imaging
• muscarinic receptor
• arecoline