Pkc

-7 ± 5 (8)

"25 ±15 (11)

-5 ±11 (7)

11 ±23 (7)

25 ± 11 (12)

10 ±11 (10)

«-CaMKH

-2 ±7 (8)

7 ± 11 (11)

8 ±10 (7)

-3 ± 16 (7)

13 ± 23 (14)

47 ±20 (10)

FIGURE 6 Percent change in phosphorylation from control for each protein kinase. Number of animals used are in parentheses. All protein phosphorylation measurements were normalized to corresponding protein kinase amounts. Shaded boxes are statistically significant. The asterisk (*) denotes a nonsignificant (p = .1) increase in autophosphorylated PKC 1 hour after contextual conditioning. Table reproduced from Atkins et al. (19).

FIGURE 6 Percent change in phosphorylation from control for each protein kinase. Number of animals used are in parentheses. All protein phosphorylation measurements were normalized to corresponding protein kinase amounts. Shaded boxes are statistically significant. The asterisk (*) denotes a nonsignificant (p = .1) increase in autophosphorylated PKC 1 hour after contextual conditioning. Table reproduced from Atkins et al. (19).

becoming activated 2-5 minutes after LTP is induced and lasting for at least 1 hour. In our behavior studies, we observed that MAPK, PKC, and a-CaMKII are activated in the hippocampus at later time points than what has been observed during hippocampal LTP. Specifically, all three kinases were activated in vivo at a time point about 1 hour later than would have been expected if LTP had occurred immediately upon training. Similar differences in the time course of activation of protein kinases in the amygdala with cued fear conditioning have also been observed (28).

This raises the interesting possibility that LTP in vivo in the relevant brain areas is happening after training but after some period of time delay. This raises three issues. One, it implies that some memory trace must be present that holds the relevant information in the CNS before it triggers LTP in the hippocampus. Second, it suggests that LTP might be involved in memory consolidation versus learning per se, an idea that we will return to in the next section. Regardless, it raises the third issue of when it is that LTP actually happens in vivo after a learning event—maybe it's later than most people think.

The important caveat to this is that at present we do not know how a 100-Hz, 1-second tetanic stimulation of hippocam-pal slices relates to an associative pairing of stimuli in a behaving animal. Thus, the temporal sequence of the biochemical events underlying learning and LTP may be the same, yet shifted to alternative kinetics during associative learning. The final alternative is that the protein kinase activation that occurs with associative training may be a result of mechanisms distinct from those recruited in LTP.

Regardless, the most parsimonious interpretation of these data with ERK, CaMKII, CREB, and the like is that they support the hypothesis that LTP is actually occurring in the CNS. In addition, they raise the important point that LTP accurately models memory. Studies of LTP led to the identification of CaMKII, CREB, ERK, and a vast array of other molecules as potential players in mammalian learning and memory. LTP-derived insights led to the formulation of the hypotheses that these molecules might be involved in memory in the behaving animal. I am confident that there will be many more examples of this truism as time progresses. The fact that LTP does not equal memory does not diminish the importance of studying LTP to help us understand memory. The fact that LTP is likely directly involved in memory formation is very important. But regardless, LTP retains its utility as a tool to gain molecular insights into the likely processes involved in memory formation as well.

A Role for LTP in Hippocampal Information Processing, Short-Term Information Storage in the Hippocampus, and Consolidation of Long-Term Memory

If LTP does not equal memory, then what does it equal? We will address this question next. In brief, current thinking among workers in the area is that LTP is obligatorily involved in hippocampus-dependent memory formation, of course. However, LTP does not equate to memory, but it is one of those processes contributing in an essential way to memory formation. It is a component mechanism utilized by the hippocampus to allow it to perform its multitudinous functions. It is a physiologic and molecular tool that allows the hippocampus to do what it needs to do. Specifically, recent work on this issue suggests a role for LTP or related processes in several of the important roles of the hippocampus that we have already discussed: in information processing, as a temporary memory store, and in long-term memory consolidation. Laboratories that have contributed monumentally to formulating current thinking in this area include those of Tim Bliss, Richard Morris, Eric Kandel, and Susumu Tonegawa.

In the next section, I will review several key studies that support a role for LTP in these three hippocampus-dependent processes. Please note this important caveat: I am going to treat hippocampal NMDA receptor-dependence as being equivalent to hippocampal LTP-dependence for illustrative purposes. This is a bit of a stretch, but not too much of one in my opinion. For example, despite decades of investigation, no one has observed that NMDA receptors function in baseline synaptic transmission in the hippocampus. The only known physiologic role of the NMDA receptor in the hippocampus is triggering LTP. Thus, manipulations that selectively block the NMDA receptor appear to be selective for blocking LTP induction but not background neuronal activity in the hippocampus (but see also reference 2). Loss of NMDA

receptor function by various manipulations in general does not appear to cause derangement of overall activity in the hippocampal circuit, but rather it causes a selective loss of the capacity to trigger changes in synap-tic strength.

An additional consideration is that equating NMDA receptor function with the triggering of synaptic change is about as close as we can get right now in terms of practicable experiments. Equating NMDA receptor activation with LTP or similar phenomena is not flawless by any means, but it is a tool that we have at our disposal that allows testing of specific predictions of a role for LTP in memory formation and information processing in the hippocampus. Loss of NMDA receptor function may cause additional effects besides loss of LTP. Loss of LTD and derangement of the postsynaptic molecular infrastructure are two prominent exceptions to keep in mind. However, loss of a particular hippocampal function upon loss of NMDA receptor function is at least consistent with the hypothesis of a role for NMDA receptor-dependent LTP in that phenomenon.

The other thing to keep in mind is that while I will focus on NMDA receptor-related studies, these are by no means are the only relevant data. Many other manipulations that block LTP also affect memory formation, consolidation, and hippocampal information processing (see reference 29 for example). The NMDA receptor manipulation is simply the one I will use for our present purposes to give an example of the types of experiments that have formed current thinking in this area.

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