Inhibition of calcium-independent phospholipase A2 activity in rat hippocampus impairs acquisition of short- and long-term memory

Abstract

Phospholipase A(2) (PLA(2)) is a family of enzymes that cleave membrane phospholipids generating important lipid mediators in signal transduction. In rat hippocampal slices, both intracellular cytosolic Ca(2+)-dependent PLA(2) (cPLA(2)) and Ca(2+)-independent PLA(2) (iPLA(2)) have been implicated in mechanisms of synaptic plasticity underlying memory processes. In mice, intraperitoneal injections of a selective iPLA(2) inhibitor impaired spatial learning. Accordingly, reduced cPLA(2) and iPLA(2) activities were found in postmortem hippocampus of patients with Alzheimer's disease. This study investigates the effects of injections of PLA(2) inhibitors directly into rat hippocampus on the acquisition of short-term (STM) and long-term memory (LTM) of a one-trial step-down inhibitory avoidance (IA) task. Wistar rats were bilaterally implanted with cannulae in the CA1 region of the dorsal hippocampus. After surgery, the rats received bilateral injections of a vehicle, or of dual cPLA(2) and iPLA(2) inhibitors (MAFP or PACOCF(3)), or a selective iPLA(2) inhibitor (bromoenol lactone) before training in IA. The animals were tested 1.5 h (for STM) and 24 h (for LTM) after training. Significant inhibition of iPLA(2) activity in rat hippocampus impaired acquisition of STM and LTM. Memory impairment did not result from neuronal death after iPLA(2) inhibition. Moreover, IA training per se increased significantly hippocampal PLA(2) activity. The present results suggest a functional effect of hippocampal PLA(2) on the neurochemistry of memory acquisition and support the hypothesis that reduced PLA(2) activity may contribute to memory impairment in Alzheimer's disease.