Summary

In this chapter, we talked about those molecular mechanisms that are uniquely involved in triggering long-lasting and very long-lasting changes in synaptic transmission in the hippocampus. We focused most of our attention on how a signal gets from the synapse to the genome, highlighting the PKA/ERK/RSK/CREB pathway as a principal player in L-LTP. We also touched upon the intriguing problem of how altered gene expression becomes manifest at just the appropriate synapse, looking at Arc mRNA as a prototype molecule.

One of the important ideas that emerged from this chapter was that we need to keep in mind that the available data support the model that altered gene expression is an induction mechanism for L-LTP. The question of whether altered gene expression contributes to the maintenance of L-LTP is still, by and large, an open one at present.

We also talked about how changes in gene expression get manifest as changes at the synapse. We in actuality developed two different models for how this happens. The first was based on increased AMPA

receptors and associated proteins at the synapse, dependent upon a triggering event such as Arc arrival at the synapse. These changes then manifested themselves as an increased synaptic strength. This proposed mechanism is a fairly straightforward read-out of increased production of synaptic components with Arc-like molecules serving as a nucleating event.

However, considering the limitations of proteins like Arc with a half-life of a few hours led us to conclude that later stages of "L-LTP" must involve additional processes. In response to this consideration, we formulated a speculative model for how self-perpetuating changes in local protein synthesis might underlie weeks-long or life-long synaptic changes.

This final section of the chapter brought us back to the issue raised at the very beginning of the chapter, that is, considering "L-LTP" as an analogue of forms of long-term memory that depend on changes in gene expression for their induction. It is very important to remember that the types of synaptic changes we have discussed in this chapter are functionally manifest as an alteration in the properties of a neuronal circuit in the CNS. Clearly, self-perpetuating molecular changes are necessary for very long-lasting effects, but the lasting effects are not the entirety of the memory. The maintenance of the synaptic change in the context of the circuit is what constitutes the memory. The self-perpetuating synaptic change is the mechanism for the maintenance of the memory.

Thus, we see an interesting parallel between L-LTP and long-term memory. Throughout the last three chapters we have made the important molecular distinction between mechanisms for the induction, maintenance, and expression of LTP. We need to make an equally important distinction between the mechanisms for the induction, maintenance, and expression of memory. The induction of memory is learning. The maintenance of long-term memory is self-perpetuating synaptic change in the context of a specific circuit. The expression of memory is the recall of the memory by sending activity through the circuit. Just as it is important to keep in mind the molecular distinctions between the induction, maintenance, and expression of LTP, it is important to keep in mind the molecular distinctions between the induction, maintenance, and expression of long-term memory.

This was an essential point that was made in Chapter 1, where a comparison was made between current learning and memory theory and the changes that need to be made in light of a better understanding of the molecular processes involved in synaptic plasticity. If you have made it this far in the book you have made it through about 75,000 words concerning the gory details of LTP physiology, biochemistry, and molecular biology. You might find it interesting to go back and reread Chapter 1 in light of all the new information you have under your belt.

This analogy between L-LTP and long-term memory is important and valid independently of whether the particular molecular mechanisms for L-LTP that we have been talking about are actually used in the behaving animal for memory itself. That does not mean that this is an uninteresting question, however! In the next chapter we will talk about the evidence for and against a role for LTP specifically in hippocampus-dependent memory formation. We also will discuss the corollary question of whether LTP has accurately modeled memory, that is, are the molecular processes involved in LTP the molecular processes involved in memory?

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