Synaptic signaling by lipids in the life and death of neurons

Synaptic activity promotes the regulated formation of lipid messengers through phospholipase-mediated cleavage of specific phospholipid reservoirs from membranes. Multiple effectors trigger the formation of lipid messengers, including neurotransmitters, membrane depolarization, ion channels, cytokines, and neurotrophic factors. Lipid messengers in turn modulate and interact with other signaling cascades, contributing to the development, differentiation, function (e.g., long-term potentiation [LTP] and memory), protection, and repair of cells in the nervous system. These relationships with other signaling cascades remain largely to be investigated. Oxidative stress disrupts lipid signaling, enhances lipid peroxidation, and initiates and propagates neurodegeneration. There is growing evidence that lipid messengers participate in the extensive interactions among neurons, astrocytes, oligodendrocytes, microglia, cells of the microvasculature, and other cells. This article provides an example of how signaling by lipids regulates critical events essential for neuronal survival and reviews the recent identification of a novel endogenous neuroprotective signaling pathway involving a docosahexaenoic acid-derived mediator.