Signal Transduction Pathways Implicated In

As we have already discussed, there are several experimental criteria that serve as a useful guideline in considering whether a hypothesis is well-supported—the block-mimic-measure criteria. In the context of E-LTP maintenance and expression (the topic of this chapter), these criteria can be formulated as follows. Criterion 1— Blocking the activity of the molecule blocks E-LTP expression. This typically is accomplished using pharmacologic inhibition, applying the inhibitor after LTP induction. Criterion 2—Directly activating the molecule should produce synaptic potentiation. This experiment is most straightforward in the context of mechanisms for LTP expression, where application of the activated form of the molecule should be capable of producing synaptic potentiation. Criterion 3— The molecule should be persistently activated (or elevated) with LTP-inducing stimulation.

Without going into a detailed review of the literature, because numerous writers including myself have reviewed these data over the years, I have summarized in the table the results from a wide variety of these types of experiments for four principal signal transduction pathways implicated in LTP: the PKA cascade, the ERK cascade, CaMKII, and PKC. The bottom line from this wide variety of studies is that, at present, a strong case can be made for a role for both persistently activated CaMKII and PKC in E-LTP maintenance. There is not unanimity of opinion on this point, and we will address some particulars of this discussion as we proceed through this chapter. Nevertheless, by and large, the block-mimic-measure criteria have been met for these molecules, and most of the rest of this chapter will deal with the mechanisms for their persistent activation in E-LTP and the targets of their actions at the synapse.

A role for persistent activation of PKA or ERK has been ruled out for E-LTP maintenance, although prolonged activation of these molecules may be involved in L-LTP induction. We will return to this discussion in the next chapter.

known isozymes that have been divided into three major subsets: conventional (a, PI, PII, and y), novel (8, e, n, 9, and |), and atypical (X and Z) (See Figure 7). Each isoform is encoded by a separate gene with the exception of the PI and PII isoforms, which are splice variants from a single gene. Each subfamily of PKC isoforms is subject to distinct control mechanisms. The conventional isoforms are regulated by calcium in concert with diacylglycerol and membrane phospholipid. The novel and atypical classes are structurally homologous but can be regulated independent of calcium. Brain subregion-and neuronal subtype-specific expression is the rule rather than the exception for the various isoforms. Almost all the various subtypes are expressed to varying degrees in the hippocampus.

Good evidence exists from Todd Sacktor's lab that a wide variety of PKC isoforms are activated in response to LTP-inducing stimulation (34). For the present purposes, we will focus on the calcium-responsive isoforms: alpha, beta, and gamma. In a later section of the chapter, we will cover PKC zeta.

One would like to begin to dissect the contributions of the various isoforms of PKC

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