Distribution of Secretory Phopholipase Group XIIA in the CNS and its role in Lipid Metabolism and Cognition

Abstract

Phospholipases A 2 (PLA 2 ) catalyze the hydrolysis of membrane phospholipids to produce free fatty acids and lysophospholipids, which have important functions in cell signaling. To date, however, little is known about differential expression and physiological functions of PLA 2 isoforms in specific brain regions. The present study was carried out to determine differential expression of PLA 2 isoforms in the prefrontal cortex (PFC) of the rat brain. Real time RT-PCR results indicated that sPLA 2 -XIIA had greater mRNA expression than iPLA 2 -VI or cPLA 2 -IVA in all brain regions, or compared to other sPLA2 isoforms, in the PFC and hippocampus. Western blots showed a 24kDa band in different regions of the adult brain, and high levels of sPLA 2 -XIIA protein expression were detected in the PFC, striatum and thalamus. The enzyme was immunolocalized to neurons, and electron microscopy showed that sPLA 2 -XIIA is present in axon pre-terminals or growth cones that did not form synaptic contacts with dendrites. Injection of antisense oligonucleotide to sPLA 2 -XIIA in the PFC resulted in increases in phospholipid but decreases in lysophospholipid molecular species, consistent with decreased catalytic activity of the enzyme, and alterations in sphingolipids. sPLA 2 -XIIA knockdown also resulted in shorter latency timings in the passive avoidance test, and higher number of errors in the attention set-shifting task, indicating deficits in working memory and attention, respectively. Together the results show an important role of sPLA 2 -XIIA in lipid metabolism and cognition. We postulate that sPLA 2 -XIIA may induce remodeling of opposing neural cell membranes to facilitate axon pathfinding and neural plasticity in the brain.