Targets Of The Persisting Signals

How is it that a persistently activated kinase or other persisting biochemical signal is converted to an enhancement of the coupling between two neurons at Schaffer-collateral synapses? This is the essential question concerning the mechanism of expression of E-LTP. Maintenance can be served by an autonomously active kinase, for example, but that persisting signal must be converted to some functional consequence at the synapse in order for synaptic potentiation to occur.

This is the issue we will focus on in this section. In considering the possible mechanisms for enhanced neuronal coupling, it is useful to think about the basics of synaptic transmission and postsynaptic responsiveness. There are three basic components of synaptic transmission—the release of neurotransmitter, the postsynaptic depolarization due to activation of ligand-gated ion channels, and the biophysical response of the postsynaptic membrane to that depolarization. Thus, potential sites for the expression of E-LTP include (1) the machinery of the presynaptic terminal involved in presynaptic calcium influx and the neurotransmitter release process, (2) the postsynaptic glutamate receptors plus their associated proteins, specifically receptors of the AMPA subtype involved in gluta-matergic responses, and (3) the potassium and sodium channels that shape the postsynaptic response to glutamatergic receptor-mediated depolarization.

I will discuss each of these three categories of effectors separately as a means of organizing the following discussion, but it is important to remember that they do not operate in isolation nor are the mechanisms mutually exclusive. In fact, evidence exists that each of these three mechanisms participates in E-LTP expression, as we discussed in the chapters on LTP physiology. However, there is a much greater abundance and variety of information and results implicating glutamate receptor regulation in LTP, and much more is known about the mechanisms relevant to this category than the other two categories. Thus, we will direct more attention to this effector system than to the other two.

A. AMPA Receptors in E-LTP

The E-LTP-associated increase in synaptic strength, that is the increase in the EPSP, clearly results in part from increased levels of postsynaptic glutamate receptor activation (reviewed in reference 59). One set of mechanisms contributing to this phenomenon is fairly well understood— enhancement of AMPA receptor function. As both PKC and CaMKII are persistently activated in E-LTP and can affect AMPA receptor function as described below, a parsimonious explanation for the increased synaptic response postsynaptically in E-LTP is increased phosphorylation of AMPA receptors and their associated proteins by these kinases.

Three specific mechanisms for augmenting AMPA receptor function, mediated by CaMKII or PKC, have been implicated as playing a part in E-LTP (see Table 3). One mechanism is that the level of AMPA receptor phosphorylation is increased during E-LTP, phosphorylation at a site that can be phosphorylated by either CaMKII or PKC. Increased phosphorylation at this site results in increased receptor current

TABLE 3 Proposed Mechanisms for Augmenting AMPA Receptor Function in E-LTP

Mechanism Likely Molecular Basis

Increased single-channel conductance Direct phosphorylation of AMPA receptor alpha subunits by

CaMKII or PKC

Increased steady-state levels of AMPAR CaMKII (+ PKC?) phosphorylation of AMPA receptor-associated trafficking and scaffolding proteins

Insertion of AMPAR into silent synapses CaMKII phosphorylation of GluR1-associated trafficking proteins

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