Platelet activating factor (PAF) in memory formation: role as a retrograde messenger in long-term potentiation

Long-term potentiation (LTP) is a neurophysiological process that has been implicated in memory formation. The elevation of intracellular Ca²⁺ levels in postsynaptic neurons, an essential step in the induction of LTP in the hippocampus, can lead to activation of the enzyme acetyl-CoA:lyso-PAF acetyltransferase that is required for PAF synthesis in neurons. Thus, during the induction of LTP, stimulation of Ca²⁺ influx by glutamate receptors would lead to a postsynaptic increase in PAF biosynthesis. A main target for PAF action in neurons is the stimulation of neurotransmitter release via Ca²⁺-dependent vesicular exocytosis, a process that occurs presynaptically. In this article we describe the evidence obtained to-date for the pre- and postsynaptic events outlined above, and demonstrate for the first time that during the induction of LTP by high-frequency stimulation (HFS) a 9-fold increase in PAF release to the extracellular environment occurs within 60 min following HFS. This finding provides the evidence that PAF can diffuse from postsynaptic sites of synthesis to presynaptic sites of action, and thus function as a retrograde messenger in the induction of LTP. Based on these data, we present a scheme in which postsynaptic glutamate receptors cooperate with presynaptic PAF receptors in a reverberating cycle that can amplify the transmission in a Hebbian synapse.