What synaptic lipid signaling tells us about seizure-induced damage and epileptogenesis

Abstract

Glutamate, the most abundant excitatory neurotransmitter in the mammalian CNS, plays a central role in many neuronal functions, such as long-term potentiation, which is necessary for learning and memory formation. The fast excitatory glutamate neurotransmission is mediated by ionotropic receptors that include AMPA/kainate and N-methyl-D-aspartate (NMDA) receptors, while the slow glutamate responses are mediated through its interaction with metabotropic receptors (mGluRs) coupled to G-proteins. During seizures, massive release of glutamate underlies excitotoxic neuronal damage as it triggers an overflow of calcium in postsynaptic neurons mediated by NMDA-gated channels. The early upstream postsynaptic events involve the activation of phospholipases, with the release of membrane-derived signaling molecules, such as free arachidonic acid (AA), eicosanoids, and platelet-activating factor (PAF). These bioactive lipids modulate the early neuronal responses to stimulation as they affect the activities of ion channels, receptors, and enzymes; and when released into the extracellular space, they can contribute to the modulation of presynaptic neurotransmitter release/re-uptake, and/or affect other neighboring neuronal/glial cells. The downstream postsynaptic events target the nucleus, leading to activation of gene-expression cascades. Syntheses of new proteins are the basis for seizure-induced sustained physiological and/or pathological changes that occur hours, days, or months later, such as synaptic reorganization and repair, and apoptotic/necrotic neuronal death. The intricate mesh of signaling pathways converging to the nucleus, and connecting upstream to downstream synaptic events, are at present the focus of many research efforts. We describe in this chapter how seizure-induced glutamate release activates the hydrolysis of membrane AA-phospholipids via phospholipase A2 (PLA2), PLC, and PLD, thus releasing bioactive lipids that, in turn, modulate neurotransmission. We discuss mechanisms through which lipid messengers, such as AA and PAF, may turn into injury mediators participating in seizure-induced brain damage.