Chapter Overview I. Targets of the Calcium Trigger
A. CaMKII in E-LTP
B. A Second Target of Calcium: PKC
C. A Final Potential Target of Calcium—Phospholipases
D. Section Summary: Mechanisms for Generating Persisting Signals in E-LTP II. Targets of the Persisting Signals
A. AMPA Receptors in E-LTP
B. Direct Phosphorylation of the AMPA Receptor
C. Regulation of Steady-State Levels of AMPA Receptors
D. Silent Synapses
F. Presynaptic Changes—Increased Release
G. Postsynaptic Changes in Excitability
III. Dendritic Protein Synthesis
In the last chapter, we discussed the complex mechanisms and biochemical "computations" involved in deciding whether an LTP-inducing level of calcium will be reached postsynaptically. In this chapter, we will deal with the first stages of those processes that are actually triggered by that calcium signal when it is attained. In essence, this chapter deals with the transition of LTP induction mechanisms into the maintenance and expression of LTP. For this chapter, we will deal specifically with the early stage of LTP, E-LTP. In the next chapter we will move on to later stages of LTP and the unique biochemical processes involved in L-LTP.
In this chapter, we begin to deal with the fundamental biochemical problem that has to be solved in order for memory to exist— the generation of a persisting biochemical signal by a transient inducing stimulus. In many ways, this is the heart of the matter for memory at the molecular level, the reduction of the problem to its smallest finite components. We will deal specifically in this chapter with the issue of how a transient calcium signal gets converted to a persisting biochemical trace in a CA1 pyramidal neuron. Almost all the mechanisms we will discuss have been studied in the context of NMDA receptor-dependent LTP, predominantly that form induced with 100-Hz tetanic stimulation. Of course, we also will draw extensively from in vitro biochemical studies of relevant molecular processes to round out our understanding of the biochemistry relevant to LTP.
A second issue we will deal with in this chapter is how the biochemical traces involved in maintaining E-LTP get converted into potentiation of synaptic transmission. These are the mechanisms of E-LTP expression. For the most part, this means discussing mechanisms of augmenting AMPA receptor function, although we also will touch on facilitation of presynaptic glutamate release and potential alterations in postsynaptic excitability.
The standard demarcation for distinguishing E-LTP from L-LTP is dependency upon new protein synthesis and altered gene expression, and I will use this criterion for defining the scope of this chapter. E-LTP is typically defined as being independent of new protein synthesis (1,2).You should realize, however, that this is by no means a universally accepted idea. Various opinions run the gamut. At one end of the spectrum is the idea that some mechanisms for E-LTP are also dependent upon new protein synthesis. A specific example of this is Todd Sacktor's data indicating that de novo synthesis of an active fragment of PKC-zeta is involved in E-LTP maintenance, and I will cover this topic in this chapter. At the other end of the spectrum is the idea that no alterations in gene expression or protein synthesis are necessary for any phase of LTP. I also will discuss this idea briefly in this chapter, and we will return to a more theoretical treatment of the idea in the last chapter of the book. Please note that no one believes that E-LTP maintenance is independent of protein synthesis—at a minimum replenishment of proteins as they are degraded is necessary for maintaining any cellular function. What is at issue is whether alterations from baseline protein synthesis (or gene expression) are necessary—hence the use of the terms "new protein synthesis" and "altered gene expression."
By and large, however, we will be limiting our discussion to mechanisms operating in E-LTP that are independent of altered protein synthesis. This interpretation is implicit to the oft-replicated observation that E-LTP can be maintained in the face of effective concentrations of protein synthesis inhibitors. This means that we will by definition be limiting our discussion in this chapter to persisting post-translational modifications of proteins. This biochemical reality helps keep the list of possible relevant mechanisms more manageable. After all, there are a finite number of possible chemical reactions in which the twenty amino acids of a protein can participate. A brief listing of known post-translational modifications of proteins1 likely will be helpful at this point:
• Phosphorylation and dephosphorylation of serine, threonine, and tyrosine side chains
• Proteolysis—breaking the peptide amide bond of the backbone
• Oxidation and reduction of cysteine side chains (includes S-S bond formation)
• Nitrosylation of tyrosine and cysteine side chains
• ADP-ribosylation of arginine side chains
• Ubiquitination of lysine side chains
• Acetylation of lysine side chains
• Prolyl cis-trans isomerization
This is the list of candidates that we get to choose from in thinking about mechanisms for generating persisting, post-translational
1I am leaving out several of the more exotic and esoteric examples, including N-terminal acylation reactions of a variety of sorts (e.g., myristoylation), C-terminal farnesylation, cysteine palmitoylation, lysine methylation, and proline hydroxylation, plus the entire category of glycosylation reactions.
biochemical signals in cells. Of course, phosphorylation has been studied the most extensively, and we'll spend most of our time talking about phosphorylation-related mechanisms. However, any and all of these are possible mechanisms for making a persisting signal in a neuron, and the resourcefulness of evolution in capitalizing on all the tools available in the toolbox is legendary. In fact, there is direct or indirect evidence for all the mechanisms listed here as being involved in synaptic plasticity in the adult CNS (references 3, 4, and 5, and the rest of this chapter), and all but the last two have been directly implicated in NMDA receptor-dependent LTP in area CA1 (so far). It will be interesting to see what the future has in store for us as our understanding increases concerning the roles of these various processes in memory storage.
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