Phospholipases A₂ (PLA₂s) represent one of the largest groups of lipid-modifying enzymes. Remarkable advances have been made during the last decade to understand their potential physiological and pathological implications. Although several PLA₂s become fully activated after calcium mobilization, it appears that, under resting conditions, several cell types maintain a high level of PLA₂ activity which is, in nature, independent of calcium variations. This review will mainly focus on the roles of calcium-independent PLA₂ (iPLA₂) enzymes in the brain and on the mechanisms by which they could influence neuronal function and integrity. Particular attention will be given to how the iPLA₂ isoform can control both the biochemical and functional properties of glutamate receptors and, consequently, synaptic plasticity and glutamate-induced excitotoxic cell damage. In this line, we will finally discuss the possibility that brain iPLA₂ deficiencies can contribute to the appearance of brain disorders through mechanisms involving tau phosphorylation and mitochondrial dysfunction. Buy this Article