Mechanisms For The Generation Of The Actual Persisting Biochemical Signals

Point number 6 begins a transition. Thus far, we have been discussing the mechanisms for regulating postsynaptic calcium and its immediate effectors, mechanism that determine if an LTP-inducing level of calcium is reached. Point 6 transitions us into the mechanisms whereby this triggering level of calcium is converted into a persisting signal that maintains LTP. As described in the beginning of the chapter, the details of these mechanisms are dealt with in Chapter 7 (for E-LTP) and Chapter 8 (for L-LTP). In addition in those chapters, we will discuss the targets of the persisting signals that result in the expression of LTP physiologically.


In this chapter, we have discussed five categories of molecular components and processes that are involved in LTP induction. It is very important not to think of

Coincidence Illustration
FIGURE 8 Four-way coincidence detection. This is an illustration of a model of one possible interaction of the NMDA receptor's activity, the cAMP gate, PKC activation of ERK, and K channel regulation by ERK. See summary in text for explanation

these in isolation from each other—they are functional categories to help organize the complex biochemical machinery of LTP induction, not compartmentalized biochemical processes in the cell! It is a useful intellectual exercise to think up ways to mix and match the categories and allow them to interact. The interactions of these various processes are what allow the synapse to serve in its role as a molecular decision maker.

We need to begin to think of the synapse as an immensely complicated information processing machine. It integrates a plethora of biochemical signals and computes, based on a number of molecular inputs, whether to trigger a lasting molecular change. This model of synaptic function allows for the necessary sophistication required for triggering memory formation in the animal in vivo. By way of providing a summary and overview for this chapter, I will finish up with a specific example of how these processes might interact. Please keep in mind that this example is illustrative and somewhat speculative.

A. Four-Way Coincidence Detection

This example is a combination of the NMDA receptor in its classical role, the cAMP gate, PKC activation of ERK, and potassium channel regulation by ERK. CaMKII activation is taken for our purposes as necessary for LTP induction, as we will discuss in the next chapter. The model is actually not even a far-fetched idea; it draws directly from data published by Manny Landau and colleagues (1, 79), Danny Winder and his collaborators (3), Tom O'Dell's group (2), and several of my colleagues (32-35). The model is schematized in Figure 8.

Imagine that LTP is going to be triggered by a back-propagating action potential (bpAP), caused in response to strong firing at a distal synapse, coupled with local synaptic glutamate. As we have discussed, this is because NMDA receptor activation is going to require bpAP-associated membrane depolarization coupled with synaptic glutamate at the synapse of interest. In addition, imagine that Kv4.2 channels would limit the capacity of the bpAP to reach the synapse and thus depolarize the NMD A receptor, except that a PLC/ PKC-coupled muscarinic ACh receptor has activated ERK and down-regulated these channels. Thus, the muscarinic receptor has gated the bpAP and allowed it to enter the relevant dendritic region. Let's say there's modest NMDA receptor activation and the calcium influx through the NMDA receptor would be insufficient to cause robust CaMKII activation (and hence LTP), except that the cAMP gate has been opened in the vicinity due to local beta-adrenergic receptor activation by NE. This amplification allows robust CaMKII activation and LTP induction.

In this example, a strong synaptic input, plus a weak synaptic input and two neuro-modulatory inputs, has uniquely triggered lasting synaptic plasticity: four-way coincidence detection. It is a molecular analogue of a common behavioral situation: an aroused animal (NE) receiving a salient environmental cue (strong synaptic input) at the peak of the theta rhythm (ACh) coupled with a second sensory signal (weak synaptic input). The resulting increase in synaptic strength might contribute to the animal forming an associative memory for the event.

It's also completely straightforward to construct a five-way coincidence detection system. All that you have to do is add one more of the components described in this chapter—synergistic activation of ERK by two receptors, BDNF modulation of presynaptic glutamate release, or Ephrin modulation of NMDA receptor function via src. With longer-lasting extracellular signals like the Ephrins or reelin or BDNF, it is easy to construct a temporal component to the model so that the synapse can determine its set-point for LTP based on its recent history, or the recent history of other nearby neurons.

The point of these examples is to illustrate how the molecular complexity of LTP induction can require that a precise and multifactorial set of conditions be met in order to trigger plasticity. This allows for sophisticated information processing at the synaptic level. It allows for complex decision making at the molecular and cellular level. The complex biochemical machinery of the synapse allows for a complicated logic to operate in determining whether a persisting effect is triggered in the CNS. Moreover, while we have focused on hippocampal LTP specifically, these issues and mechanisms are almost certainly involved in hippocampus-dependent learning in the intact animal and at a variety of sites outside the hippocampus, for example the cortex and amygdala. We will return to this issue in Chapter 9.

As a final parting comment, I will note that in my estimation the Hebb model concerning activity-dependent synap-tic plasticity in the CNS is inadequate. Strengthening of synaptic connections simply based upon repetitive firing is insufficient to account for memory formation in my opinion. This line of thought comes out of considering all the many processes we have discussed in this chapter. The molecular complexity of LTP induction has implications for thinking about memory formation in general terms. The synapse is a complex signal integration machine. To integrate information and decide whether to change its state, it responds to multiple signals, and its recent history. It's not just static and it's not just Hebbian. I posit that, in the functioning hippocampus, one presynaptic terminal merely consistently or repeatedly participating in the firing of a postsynaptic neuron typically is not enough to trigger plasticity—many more factors come into play, factors that are critical in allowing the synapse sufficient computational power to perform sophisticated information processing.


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Biochemical Thinking Map

Autonomous Kinases in the PSD J. David Sweatt, Acrylic on canvas, 2002

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