Radiant Thinking Theory

In this chapter we will discuss the mechanisms unique to inducing and maintaining the long-lasting, late phase of LTP. This is an exciting, wide-open area of LTP research right now, one of those areas where it is clear that important work is underway but where the surface has just been scratched in terms of our understanding.

L-LTP is defined in terms of an enduring, protein synthesis-dependent form of synap-tic potentiation in area CA1, as I will describe in more detail later. However, the phrase "L-LTP" is in some ways, and perhaps in its most meaningful way, an allegory of long-term memory in the behaving animal. The particular mechanisms that are being worked out to explain L-LTP

are likely to have impact far beyond understanding L-LTP at Schaffer/collateral and perforant-path synapses. This is one reason that this area of LTP research has a slightly different "feel" to it than the other areas we have been discussing (LTP physiology and E-LTP biochemistry, for example).

This area of LTP research is frequently discussed as an analogue of long-term memory as opposed to being limited to a description of a specific neuronal plasticity phenomenon. Many investigators study E-LTP in an effort to explain that specific phenomenon in physiologic and molecular terms, while frequently investigators studying L-LTP think of "L-LTP" as more of an umbrella term that encompasses gene regulation-dependent long-term plastic changes in the adult CNS. When I do an E-LTP experiment, I am doing an experiment to understand E-LTP. When I do an L-LTP experiment, I may be doing a more general experiment to understand the role of altered gene expression, protein synthesis, and structural changes in mediating long-term changes at synapses.

A couple of practical factors feed into this. One is that L-LTP experiments are hard to do. A hippocampal slice experiment to study L-LTP lasts about 7 hours, so you can do one experiment per slice rig per day, and as with any experiment that long there is the inevitably low yield. The alternative is to study L-LTP in vivo, which is of course also quite labor-intensive. Consequently, there have not been large numbers of L-LTP experiments published, and investigators in the area are more willing to mix results from various paradigms and preparations in order to gain insights into the phenomenon of interest. Thus, the unifying theme becomes the gene expression/protein synthesis aspect instead of the particulars of the experimental design itself. I will follow this philosophy in this chapter as well, and draw examples from outside the CA1 region of the hippocampus in several instances. In particular, many of the experiments I will draw from were performed using dentate gyrus.

A second practical consideration is that it seems obvious that understanding the regulation of gene expression in the adult CNS is going to be relevant to understanding long-term plasticity in some way, shape, or form. This gives workers in the area a little more license to investigate the regulation of gene expression per se, and to discuss it in the context of its likely relevance to L-LTP. This will, of course, change as we get a better definition of exactly which long-lasting synaptic phenomena are relevant in the behaving animal. But, for the present, we are in an early enough stage so that the fundamental synaptic processes that are subject to ongoing nucleus-dependent regulation are still being defined. We can often discuss them under the rubric L-LTP.

For the sake of balance, I should also point out that some investigators believe that all this discussion of gene expression is much ado about nothing, and that self-reinforcing protein-based mechanisms are sufficient to explain even life-long synaptic alterations. There is nothing wrong with this perspective from a theoretical standpoint. The question is whether or not evolution incorporated mechanisms of altered gene expression into the systems of long-lasting synaptic plasticity. This question is still under investigation. For this reason, I will start the chapter with a brief overview of the data indicating that altered gene expression is involved in triggering late stages of LTP.

The rest of the chapter will be divided into three additional sections. The first major section deals not only with NMDA receptor coupling to the genome but also with receptor-effector coupling mechanisms in the context of transcriptional regulation. We then will proceed in the second section to some identified gene targets in L-LTP and raise the issue of how the products of these genes get to the right synapses. Finally, I will speculate about likely read-outs of altered expression of these target genes— suggesting that these changes mediate structural and morphological changes in the neuron. The basic model for the third section is that altered expression of gene products gets translated into structural changes at the synaptic spine and altered connectivity of the neuron. Ultimately these changes are manifest as changes in the synap-tic circuit in which the neuron resides.

In the context of our systematic nomenclature, in this chapter we will focus largely on the induction mechanisms of L-LTP, exploring how a triggering calcium signal gets converted into a genomic read-out. This is a fascinating area of current investigation and the area for which the most relevant data are available. The maintenance and expression mechanisms of L-LTP are still highly speculative at this point, and for this reason will be dealt with in less detail.

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