Candidate Retrograde Signaling Molecules

As described in the text, biochemical evidence makes it clear that molecular changes occur in both the presynaptic and postsynaptic compartments. While the existence of changes in both compartments does not resolve the important issue of the precise locus of increased synaptic strength, the existence of presynaptic biochemical changes that depend on postsynaptic events for their induction makes clear the necessity of a retrograde signaling mechanism of some sort. How does the postsynaptic cell communicate with the presynaptic terminal? The principal requirement is that the retrograde messenger must be able to traverse the synapse, and this could happen through either diffusion of a molecule or a direct physical coupling of molecules across the synapse (see figure). These are, of course, not mutually exclusive possibilities.

There is considerable evidence available supporting the existence of diffusible messengers that can serve as retrograde signaling molecules. Popular candidates include nitric oxide free radical (NOO, superoxide anion (O2-), and arachidonic acid (AA). These molecules have in common that they are able to cross cell membranes, and thus can be generated in the postsynaptic cell and diffuse across to local presynaptic compartments to effect changes. Their diffusion is, of course, not limited to the presynaptic terminal they are directly activated by, but rather they may also diffuse to other local synapses. We will return to the mechanisms for generating these compounds and their likely targets in the next two chapters.

A different concept for signaling is to have a protein complex that physically links the postsynaptic compartment with the presynaptic compartment. A requirement for this type of signaling is that a post-translational modification of a postsynaptic cytoplasmic domain of the complex must be able to transduce, presumably through a conformational change, a signal to the presynaptic compartment. This type of mechanism is much more speculative at present. However, cell adhesion molecules such as integrins have the necessary signal-transducing capacity. These proteins traverse the membrane and

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