Ltp Can Be Divided Into Phases

Contemporary models divide very long-lasting LTP (i.e., LTP lasting in the range of 5 to 6 hours) into at least three phases. LTP comprising all three phases can be induced with repeated trains of high-frequency stimulation in area CA1 (see Figure 7), and the phases are expressed

High Frequency Action Potentials

FIGURE 5 Increased action potential firing over the course of TFS. (A) The TFS protocol and TFS-induced LTP in mouse hippocampal slices. (B) Electrode placement configuration for recording EPSP and population spikes simultaneously during TFS. (C) Representative traces in response to TFS from a hippocampal slice. Note the difference in the population spike between the first and 18th stimulation of the stimulation paradigm. (D) Quantitation of increased spike amplitude during TFS. Population spike amplitudes recorded in stratum pyramidale of hippocampal area CA1 during theta-frequency stimulation are plotted normalized to EPSP slope. Slices showed a progressive increase in spike generation during the first two-thirds of TFS. Data and figures courtesy of Joel Selcher.

FIGURE 5 Increased action potential firing over the course of TFS. (A) The TFS protocol and TFS-induced LTP in mouse hippocampal slices. (B) Electrode placement configuration for recording EPSP and population spikes simultaneously during TFS. (C) Representative traces in response to TFS from a hippocampal slice. Note the difference in the population spike between the first and 18th stimulation of the stimulation paradigm. (D) Quantitation of increased spike amplitude during TFS. Population spike amplitudes recorded in stratum pyramidale of hippocampal area CA1 during theta-frequency stimulation are plotted normalized to EPSP slope. Slices showed a progressive increase in spike generation during the first two-thirds of TFS. Data and figures courtesy of Joel Selcher.

sequentially over time to constitute what we call LTP. Late LTP (L-LTP) is hypothesized to be dependent for its induction on changes in gene expression, and this phase of LTP lasts many hours. Early LTP (E-LTP) is likely subserved by persistently activated protein kinases, as we will discuss in Chapter 7, and starts at around 20 minutes or less post-tetanus and is over in about 2-3 hours. The first stage of LTP, generally referred to as short-term potentiation, is independent of protein kinase activity for its induction and lasts about 30 minutes. I prefer to refer to the first stage of LTP as Initial LTP (I-LTP) to emphasize that it is a persistent form of NMDA receptor-dependent synaptic plasticity that is induced by LTP-inducing tetanic stimulation and is a prelude to E-LTP and L-LTP (see reference 21). We will not really discuss I-LTP (aka STP) much more in this book because the mechanisms for its induction are essentially a complete mystery at present.

Two different groups have proposed an additional phase of LTP, intermediate LTP (22, 23). Unfortunately these two groups are not referring to the same thing, in all likelihood. At this time, I am not incorporating an intermediate phase of LTP into our discussion because intermediate-LTP might be explained as a prolonged form of E-LTP. Also, even though there is generally a consensus about different mechanisms for

FIGURE 6 GABA-B receptors in temporal integration with TBS. This figure presents one model for the increased excitability that occurs during TBS, based on autoinhibition at GABAergic inputs onto CA1 pyramidal neurons during the period of stimulation.

E-LTP and L-LTP, it is unclear where intermediate LTP might fit into this scheme.

Readers may note some degree of ambiguity in the times specified for each phase of LTP. This is in part because the phases are very descriptive and different labs often use slightly different conditions for their LTP experiments. For example, for technical reasons, most L-LTP experiments are performed at room temperature or 27-28°C because it is much easier to maintain a healthy slice for many hours at these lower temperatures. Many E-LTP experiments, especially those involving direct biochemical measurements, are performed at 32-35°C. Comparing studies done at different temperatures is complicated by the pronounced temperature-dependence of essentially all chemical reactions—any physical chemist far afield enough to be reading this book will remember that this is described by the Arrhenius Equation. Plugging some back-of-the-envelope numbers into this equation shows that a doubling of reaction

Phases Ltp

Time (minutes)

FIGURE 7 Immediate, early, and late LTP. (A) Real data from a late-phase LTP experiment. Courtesy of Eric Roberson. (B) A cartoon adaptation of the same data approximating the Initial, Early, and Late stages of LTP. Adapted from Roberson, English, and Sweatt (21).

Time (minutes)

FIGURE 7 Immediate, early, and late LTP. (A) Real data from a late-phase LTP experiment. Courtesy of Eric Roberson. (B) A cartoon adaptation of the same data approximating the Initial, Early, and Late stages of LTP. Adapted from Roberson, English, and Sweatt (21).

rate for a change from room temperature to 32°C is fairly common for biochemical reactions. For these many reasons, it is difficult to try to compare experiments done at one temperature to experiments done at another. L-LTP may start at 3 hours at room temperature, 1.5 hours at 32 degrees, and 45 minutes in vivo.

A. E-LTP and L-LTP—Types Versus Phases

I use E-LTP and L-LTP to refer to different temporal phases of LTP. By my definition, these phases are subserved by different maintenance mechanisms of different time-courses and durations. By phase, I mean a period of potentiation subserved by a unique mechanism. These two phases of LTP—E-LTP and L-LTP—are not exclusive of each other. In fact, my model is that E-LTP is ongoing while L-LTP is developing, and that one supplants the other over time. This has certain theoretical implications that are discussed in more detail in reference 21. I emphasize these definitions here because they are very important as we transition to molecular mechanisms in the next chapters. These definitions contain an underlying assumption about the biochemistry of LTP that is an organizing principle for the rest of the book.

The terms E-LTP and L-LTP, however, have been used in a slightly different fashion as well, in particular as popularized by the Kandel laboratory. The Kandel laboratory and others also use a terminology that divides the NMDA receptor-dependent form of LTP in area CA1 into E-LTP and L-LTP. E-LTP and L-LTP in this terminology refer to what I would characterize as two subtypes of LTP—a transient form (typically lasting 1-2 hours) and a long-lasting form (lasting at least 5 hours or more). The latter form of LTP is characterized by its dependence on intact protein synthesis, and the induction of this form of LTP requires delivery of multiple tetanic stimuli. E-LTP in this alternative nomenclature is induced by fewer tetanic stimuli and is protein-synthesis-independent. The disadvantage in my mind of this latter terminology is that it doesn't appear to allow for E-LTP to exist as a preliminary phase preceding L-LTP in time. In the Kandel-like usage, E-LTP and L-LTP are really being defined as different types of LTP, not as temporal phases of LTP. In the way I use the words, I assume that multiple tetani induce both E-LTP and L-LTP, and that E-LTP maintains the potentiation until L-LTP develops. Whether E-LTP and L-LTP coexist in the same cell is an open question, but I want to make clear to the reader to keep in mind that two slightly different variations in the use of E-LTP and L-LTP exist in the literature.

The thing that I like about the Kandel laboratory's use of the terms E-LTP and L-LTP is that their usage emphasizes that different and unique things happen with multiple tetani. Multiple, spaced tetani elicit very long-lasting LTP and appear to recruit a unique protein synthesis-dependent mechanism for L-LTP. This is a great example of temporal integration—tetani delivered in close temporal sequence with other tetani appear to be able to trigger a uniquely long-lasting event: L-LTP. This is a cellular analog to the graded acquisition of memory—as we discussed in the first two chapters multiple training trials elicit more robust and long-lasting memory. The E-LTP/L-LTP dichotomy drawn by the Kandel lab highlights this attribute, and that is, I believe, the rationale behind their use of the terms. Again, I point this out to help avoid confusion because of the different applications of the terms E-LTP and L-LTP. This is particularly important because later on in this section and in Chapter 12 I will discuss some theoretical implications of LTP having different phases. In these sections, I will be referring to E-LTP and L-LTP as being at different points on a temporal continuum, not as different types of LTP.

Before turning to a discussion of some implications of LTP having phases, I must introduce one final set of three terms— three terms widely used and abused in the LTP literature. These terms arose from pharmacological inhibitor studies of LTP, and I will go through these types of studies in a moment. However, for now I will simply introduce the terms.

Induction refers to the transient events serving to trigger the formation of LTP. Maintenance, or more specifically a maintenance mechanism, refers to the persisting biochemical signal that lasts in the cell. This persisting biochemical signal acts upon an effector, for example a glutamate receptor or the presynaptic release machinery, resulting in the expression of LTP.

It is important to keep in mind that, depending on the design of the experiment, induction, maintenance, and expression could be differentially inhibited (see Figure 8). The simplest type of experiment doesn't do this—imagine, for example, that you apply an enzyme inhibitor (or knockout a gene) before, during, and after the period of LTP-inducing high-frequency stimulation and find that your manipulation blocks LTP. You cannot distinguish whether the missing activity is required for the induction, the expression, or the maintenance of LTP. To distinguish among these possibilities, imagine instead applying the inhibitor selectively at different time points during the experiment. If you apply the inhibitor only during the tetanus and then wash it out, but it blocks the generation of LTP, you can conclude that the enzyme is necessary for LTP induction. If you apply the inhibitor after the tetanus, and it reverses the potentiation, it may be blocking either the maintenance or expression of LTP, as was nicely illustrated in an early experiment by Malinow, Madison, and Tsien (24) where they applied a protein kinase inhibitor after LTP induction. In this experiment, transient application of a kinase inhibitor after tetanus blocked synaptic potentiation, but the potentiation recovered after removal of the inhibitor. This is a blockade of LTP expression. However, if the kinase inhibitor had caused the potentiation to be lost irreversibly, the inhibitor would then by definition have blocked the maintenance of LTP.

Sweatt Ltp Maintenance
FIGURE 8 Induction, maintenance, and expression of LTP. This schematic illustrates the different experimental approaches to dissecting effects on the biochemical mechanisms subserving LTP induction, maintenance, or expression. See text for additional details.

Was this article helpful?

0 0
Eliminating Stress and Anxiety From Your Life

Eliminating Stress and Anxiety From Your Life

It seems like you hear it all the time from nearly every one you know I'm SO stressed out!? Pressures abound in this world today. Those pressures cause stress and anxiety, and often we are ill-equipped to deal with those stressors that trigger anxiety and other feelings that can make us sick. Literally, sick.

Get My Free Ebook


Post a comment