Synaptic tagging and long-term potentiation

Repeated stimulation of hippocampal neurons can induce an immediate and prolonged increase in synaptic strength that is called long-term potentiation (LTP)—the primary cellular model of memory in the mammalian brain1. An early phase of LTP (lasting less than three hours) can be dissociated from late-phase LTP by using inhibitors of transcription and translation2–8. Because protein synthesis occurs mainly in the cell body9–12, whereas LTP is input-specific, the question arises of how the synapse specificity of late LTP is achieved without elaborate intracellular protein trafficking. We propose that LTP initiates the creation of a short-lasting protein-synthesis-independent 'synaptic tag' at the potentiated synapse which sequesters the relevant protein(s) to establish late LTP. In support of this idea, we now show that weak tetanic stimulation, which ordinarily leads only to early LTP, or repeated tetanization in the presence of protein-synthesis inhibitors, each results in protein-synthesis-dependent late LTP, provided repeated tetanization has already been applied at another input to the same population of neurons. The synaptic tag decays in less than three hours. These findings indicate that the persistence of LTP depends not only on local events during its induction, but also on the prior activity of the neuron.