Ltp Does Not Equal Memory

The "strong" hypothesis that LTP equals memory makes a number of predictions. We can frame these in the general form that we have been using throughout the book— block, mimic, and measure. Thus,

The block experiment—agents that block LTP should block memory formation. A corollary of this is that agents that enhance LTP should enhance memory. The mimic experiment—inducing LTP in the right place in the brain should cause a behavioral change indistinguishable from learned behavior. A variation of this idea is that saturating LTP at the right synapses should interfere with memory formation utilizing those synapses—a behavioral variation of an "occlusion" experiment. Finally, the measure experiment—when an animal learns, LTP should be observable in its CNS. A variation of this prediction is that molecular events associated with LTP induction should be observable in the animal's CNS in association with memory formation.

In this chapter I will provide a brief overview of the available data testing whether LTP = Memory, using these categories of experiments as the organizing basis for the chapter.

I should note before I begin that the discussion will not be exhaustive because this topic has received considerable attention already in the literature. Obviously, this has been one of the hottest topics around since the first report of LTP by Bliss and Lomo. I have listed several reviews evaluating the role of LTP in memory formation in the references (2-5). In particular, I point you to the recent review from Richard Morris's group as an additional reading (2)—it is executed with the typical depth and clarity that Richard brings to his varied efforts.1

A. The Block Experiment

Many, many experiments that touch on the issue of whether experimental manipulations that block LTP also block learning and memory have been published. For our purposes here, I am going to focus on experiments using genetic manipulation of mice because this type of experimental approach has several appealing aspects. For one thing, this is a fairly absolute manipulation—either the gene is there or it isn't. Dosages and efficacy are not nearly as much a concern with knockout and transgenic animals, versus drug studies, although, of course, cellular compensation and compensatory changes in homologous gene expression levels are a caveat to the approach (see Box 1). Another reason I like genetic manipulation experiments for our purposes is that, in almost every case, the LTP experiments and the behavior experiments were done side by side in the same lab group and using the same animals. Even in those cases where background strain effects or molecular compensation are factors, molecularly identical or even individually identical animals were used for both the LTP and the behavior studies in essentially every case. The LTP and behavior studies are then as directly comparable as can be achieved as a practical matter.

In our thought experiment, we are going to posit that hippocampal LTP equals hippocampus-dependent memory. If LTP gets better, memory should get better. If

1I wrote this chapter in July 2002. When I started to write this chapter, I accumulated all the relevant references I could find, and one in particular stuck out —the review by Martin, Grimwood, and Morris "Synaptic Plasticity and Memory: An Evaluation of the Hypothesis" (2). I had never read it (sorry Richard), and I set it aside. It was clear from reading the abstract that it dealt with many of the same issues that I was going to be dealing with in this chapter, and I wanted to conduct an exercise using it. I wrote this chapter without referring to the Martin et al. review, and after writing the chapter I went back and read Martin et al. as a compare-and-contrast exercise to see how my thinking compared to theirs. Part of my rationale was that it has been my experience that two people assessing the same question independently tend to come up with a broader range of ideas than if one leads and the other follows. Thus, I didn't want to deny myself the opportunity of potentially coming up with different ideas than Richard and his colleagues.

After drafting the chapter and going back to read their review my response was twofold. First, I was astonished at the degree of similarity in how they had organized their thinking and writing about the topic, relative to my own writing in this chapter. I took this as a good sign. Second, I was relieved that my thinking on the general role of LTP in memory was in line with theirs. It's nice to have your thoughts match up with one of the leading scholars and thinkers in the field, in this case Richard Morris. The congruence is perhaps not surprising because, of course, I have read most of Richard's primary publications in the area, and his work has always greatly influenced me.

I promised myself that I would not go back and substantially change the chapter after reading Martin et al., and I was able to adhere to that. Nevertheless, after reading their review I added a couple of mutants to Table 1 that I had missed and modified the section on the "mimic" experiment based on the historical clarification available in Martin et al. Also, I went back to Chapter 7 and added some discussion to the synaptic tagging Box because reading Martin et al. highlighted in my mind the potential role of synaptic tagging in temporal integration.

I relate this anecdote for three reasons. First, one of the responsibilities of a scholarly writer is to acknowledge priority in publication, which is certainly applicable here. The second purpose is to acknowledge the profound influence that Richard has had on my thinking and everyone else's in the field. He has been and continues to be a pioneering experimentalist and thinker on the issue of the role of synaptic plasticity in memory formation. Finally, I relate the story because I think that this sort of exercise is a very interesting and edifying experience, and that students should attempt it routinely. Pick a review by one of the leaders in your field and "blindly" outline how you would write a review on the same topic. Go back and compare your outline with their review. What holes did you have in your outline? Are your ideas on the important topics and future directions similar to theirs? Did you think of anything that they didn't?

One day, when you're an old guy like me, you can enjoy the luxurious fun of having your exercises published in a book, such as happened in this case.

LTP gets worse, memory should get worse. To test these predictions, I surveyed the available literature and found those publications where both LTP and spatial memory had been assessed in a knockout or transgenic animal. Generally speaking, the LTP studied is NMDA receptor-dependent (with one exception), in Area CA1 mostly (but also dentate gyrus in some cases), and induced with 100-Hz stimulation or theta-frequency stimulation. The memory paradigms are almost all either Morris water maze or contextual fear conditioning. I tried, to the best of my ability, to eliminate strains where pronounced structural deficits or neurodegenerative processes occurred—this eliminated a number of disease models, for example.

About 50 different molecules were knocked out, genetically inhibited, or aberrantly expressed in the studies I surveyed.2 I have arranged the results of the survey

2This is about 0.1-0.2 % of the genome, amazingly enough. Moreover, as a practical matter, it is difficult to find publications for animals that had no phenotype in either LTP or memory, so many of these that exist would have been missed. In addition, embryonic lethality or mutations that cause gross pathological changes are eliminated from consideration. Thus, Table 1 may in fact represent a reasonably broad sampling of the genome, at least for those genes that are experimentally tractable using these approaches.

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