Presynaptic Versus Postsynaptic Mechanisms

One of the most intensely studied and least satisfactorily resolved aspects of LTP concerns the locus of LTP maintenance and expression. One component of LTP is an increase in the EPSP, which could arise from somehow increasing glutamate concentrations in the synapse or by increasing the responsiveness to glutamate by the postsynaptic cell (see Figure 1). In short, the "pre"-versus-"post" debate is whether the relevant changes reside presynaptically, manifest as an increase in neurotransmitter release or similar phenomenon, or post-synaptically, as a change in glutamate receptor responsiveness, etc. Over the last

FIGURE 1 Potential sites of synaptic modification in LTP.

15 years or so, numerous experiments were performed to try to address this question, and as of yet there is no clear consensus answer. Popularity of the "Pre" hypothesis versus the "Post" hypothesis has waxed and waned, and this oscillation may continue for some time yet. In the next few paragraphs, I will summarize a few representative findings to give a little background on the issues. Those readers looking for an interesting "homework" assignment would find the following exercise edifying: in one sitting read the recent papers by Choi, Klinguaf, and Tsein (2); Bolshakov, Golan, Kandel, and Siegelbaum (3); and Nicoll and Malenka (4). This will give you a feel for the nature of the ongoing debate, and also illustrate that a lot of really smart people have been working on the problem and have yet to reach a consensus.

In some of the earliest studies that began to get at LTP mechanistically, it became clear that infusing compounds into the postsynaptic cell led to a block of LTP. A few of these studies involving calcium chelators were described in the last chapter, and some studies investigating protein kinases are described in Box 1 in this chapter. If compounds that are limited in their distribution to the postsynaptic compartment block LTP, the most parsimonious hypothesis is that LTP resides postsynaptically.

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