Role For Calcium Influx In Nmda Receptordependent

In contrast to the story with mossy fiber-LTP, NMDA receptor-dependent LTP at Schaffer-collateral synapses has achieved a broad consensus of a necessity for elevations of postsynaptic calcium for triggering LTP (21). In fact, this is one of the few areas of LTP research where there is almost universal agreement, and for that reason I am choosing this as the proper topic with which to end this chapter. In a very real sense, this topic is a break-point in the book, where we will transition from established thinking to more speculative areas. The elevation of postsynaptic calcium as a trigger for LTP is also appropriate as a transitional topic because this is the point at which biochemically things become much more complex—most of the next four chapters will deal with the complexities of regulating the generation of the calcium signal and the plethora of events that this unique signal triggers.

But for one last section we can sit back and enjoy the harmony of consensus opinion, at least until I add in a few dissonant notes to spice up the composition a bit.

The case for a role for elevated postsynaptic calcium in triggering LTP is quite clear-cut and solid. It is well-established and has been reviewed adequately a sufficient number of times (22-25), so I will only overview the evidence here. Injection of calcium chelators postsynaptically blocks the induction of LTP. Inhibitors of a variety of calcium-activated enzymes also block LTP induction, as we will discuss extensively in chapters 6 and 7. Fluorescent imaging experiments using calcium-sensitive indicators have clearly demonstrated that postsynaptic calcium is elevated with LTP-inducing stimulation. Elevating postsynaptic calcium is sufficient to cause synaptic potentiation (although I must say there has been a little bit of controversy on this point). Thus, the hypothesis of a role for postsynaptic calcium elevation in triggering LTP has met the three classic criteria (block, measure, mimic) that we discussed in the last chapter and thus apparently is on solid ground.

I emphasize this, and the fact that there really is no disagreement about this conclusion, because something so well-established will serve nicely as a basis for a critique of the logic of this type of hypothesis testing. William of Ockham formulated Occam's Razor in the context of evaluating competing hypotheses. Basically, Occam's Razor states that when competing hypotheses are being evaluated, choose the one that is the simplest and still compatible with the available data. There is no doubt this is solid reasoning. The simplest hypothesis that is consistent with the available data described in the last paragraph is that elevations of postsynaptic calcium trigger LTP. However, consider the alternative interpretation of the block experiment, where the injection of calcium chelators postsynaptically blocks LTP induction. Say you hypothesize that what is really happening is that maintaining a tonic, low level of calcium is necessary to maintain the appropriate biochemical state of the cell. You think that chelating calcium disrupts this baseline process, which is not involved in LTP induction but is prerequisite for allowing LTP to happen. You say that the observed calcium elevation is an epiphenomenon not involved in LTP induction, and the sufficiency of postsynaptic calcium for triggering LTP is in question.

This is clearly not the most parsimonious interpretation of the data, a la Occams Razor. It requires much more mental gymnastics to justify. However, it is consistent with the available data and a perfectly tenable hypothesis. My point here is that the logic of hypothesis testing is not absolute, nor is it flawless. Testing the "big three" predictions experimentally is just about all you can do, and the more different ways you test them the better. However, we must always keep in mind that the underlying biology may not cooperate with us, and that things may be more complicated than we imagine. This of course becomes more and more of an issue the less data you have relevant to any hypothesis—in other words, for most of the rest of the topics we will be covering in this book. It also is important to keep in mind that, no matter what the area of investigation, the specific caveats for LTP experiments generalize to the rest of scientific investigation as well.

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