types of peptides were used to inhibit CaMKII activation in these studies. In one series of studies the investigators used the pseudosubstrate peptide CaMKII(273-302), which inhibits CaMKII by mimicking the autoinhibitory domain (26). In a separate series of experiments, a different type of approach was used—the infusion of calmodulin-binding peptides (27). These peptides bind to the calcium signal-transducing protein calmodulin and inhibit its activation of downstream targets including CaMKII. The results from both experiments are consistent with a role for postsynaptic signal transduction events in LTP induction in general and suggest a role for CaMKII specifically. It turns out that subsequent work has shown that both manipulations are doing more than just blocking CaMKII activation because both types of peptides can affect other relevant signal transduction cascades. Nevertheless, these were key findings at the time, motivating pursuit of the CaMKII system as
a player in LTP induction, and a wide variety of subsequent work has supported a role for CaMKII activation in LTP.
Not too long afterward, however, evidence began to accumulate suggesting that there were presynaptic changes involved in LTP expression as well. For example, various types of "quantal" analysis that had been successfully applied at the neuromuscular junction to dissect presynaptic changes from postsynaptic changes suggested that LTP is associated with changes presynaptically. In a series of investigations, several laboratories used whole-cell recordings of synaptic transmission in hippocampal slices and found an increase in the probability of release, a strong indicator of presynaptic changes in classic quantal analysis (5-8). These findings fit nicely with earlier studies from Tim Bliss's laboratory suggesting an increase in glutamate release in LTP as well (8). OK, so why not just say that there are changes both presynaptically and postsynaptically? The rub came in that some of the quantal analysis results seemed to exclude the occurrence of post-synaptic changes.
These findings in the early 1990s ushered in an exciting phase of LTP research that was important independent of the pre-versus-post debate per se. If there are changes presynaptically but these changes are triggered by events originating in the postsynaptic cell, as the earlier inhibitor-perfusion experiments had indicated, then the existence of a retrograde messenger is implied. A retrograde messenger is a compound generated in the postsynaptic compartment that diffuses back to and signals changes in the presynaptic compartment—the opposite (retrograde) direction from normal synaptic transmission. Moreover, if the compound is generated intracellularly in the postsynaptic neuron, then the compound must be able to traverse the postsynaptic membrane somehow. The data supporting presynaptic changes in LTP implied the existence of such a signaling system, and this hypothesis launched a number of interesting and important experiments to determine what types of molecules might serve such a role— some of these are highlighted in Box 2.
However, in the mid-1990s the pre/post pendulum began to swing back in the opposite direction, toward the postsynaptic
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