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FIGURE 6 APV block of LTP. These data are from recordings in vitro from mouse hippocampal slices, demonstrating the NMDA receptor-dependence of tetanus-induced LTP. Identical high-frequency synaptic stimulation was delivered in control (filled circles) and NMDA receptor antagonist (APV, open triangles) treated slices. Data courtesy of Joel Selcher.

work has shown that an NMDA receptor-independent type of LTP can be induced in area CA1, and elsewhere in the hippocampus (mossy fibers to be precise), as well as other parts of the CNS. We will return to a brief description of these types of LTP at the end of this chapter, but for now we will continue to focus on NMDA receptor-dependent types of LTP.

Early studies of LTP used mostly high-frequency (100-Hz) stimulation, in repeated 1-second-long trains, as the LTP-inducing stimulation protocol. Even though these protocols are still widely used to good effect, it is clear that such prolonged periods of high-frequency firing do not occur physiologically in the behaving animal. However, LTP can also be induced by stimulation protocols that are much more like naturally occurring neuronal firing patterns in the hippocampus. To date, the forms of LTP induced by these types of stimulation have all been found to be NMDA receptor-dependent in area CA1. Two popular variations of these protocols are based on the natural occurrence of an increased rate of hippocampal pyramidal neuron firing while a rat or mouse is

100-Hz 100-Hz 100-Hz 100-Hz

100-Hz 100-Hz 100-Hz 100-Hz

10 msec between pulses

• 5-Hz burst frequency

■ 3 trains, 20-sec intertrain interval

10 msec between pulses

• 5-Hz burst frequency

■ 3 trains, 20-sec intertrain interval

(mini

FIGURE 7 LTP Triggered by theta-burst stimulation in the mouse hippocampus. (A) This schematic depicts theta-burst stimulation. The LTP induction paradigm consists of three trains of 10 high-frequency bursts delivered at 5 Hz. (B), LTP induced with theta-burst stimulation (TBS-LTP) in hippocampal area CA1. The three red arrows represent the three TBS trains. Data courtesy of Joel Selcher.

exploring and learning about a new environment. Under these circumstances hippocampal pyramidal neurons fire bursts of action potentials at about 5 bursts/sec (i.e., 5 Hz). This is the "theta" rhythm that was discussed in the last chapter. One variation of LTP-inducing stimulation that mimics this pattern of firing is referred to as theta-frequency stimulation (TFS), which consists of 30 seconds of single stimuli delivered at 5 Hz. Another variation, theta-burst stimulation (TBS) consists of three trains of stimuli delivered at 20-second intervals, each train is composed of ten stimulus bursts delivered at 5 Hz, with each burst consisting of four pulses at 100 Hz (see Figure 7). We will return to these types of LTP induction protocols in Chapters 5 and 9, where we will discuss modulation of LTP induction and the role of LTP in learning in the animal. For now, it is worth noting that these patterns of stimulation, which are based on naturally occurring firing patterns in vivo, lead to LTP in hip-pocampal slice preparations as well.

A. Pairing LTP

Of course, one can use much more sophisticated electrophysiologic techniques than extracellular recording to monitor synaptic function. Intracellular recording and patch clamp techniques that measure electrophysiologic responses in single neurons have also been used widely in studies of LTP, and as with field recordings, you can use these techniques and observe LTP (see Box 2). Of course, these types of recording techniques perturb the cell that is being recorded from and lead to "rundown" of the postsynaptic response in the cell impaled by the electrode. This limits the duration of the LTP experiment to however long the cell stays alive— somewhere in the range of 30 minutes to an hour for an accomplished physiologist. Regardless, in these recording configurations you can induce synaptic potentiation using tetanic stimulation or theta-pattern stimulation and measure LTP as an increase in post-synaptic currents through glutamate-gated ion channels, or as an increase in postsynaptic depolarization when monitoring the membrane potential.

Control of the postsynaptic neuron's membrane potential with cellular recording techniques also allows for some sophisticated variations of the LTP induction paradigm. In one particularly important series of experiments, it was discovered that LTP can be induced by pairing repeated single presynaptic stimuli with postsynaptic membrane depolarization, so-called "pairing" LTP (6). (See Figure 8.)

The basis for pairing LTP comes from one of the fundamental properties of the NMDA receptor (see Figure 9). The NMDA receptor is both a glutamate-gated channel and a voltage-dependent one. The simultaneous presence of glutamate and a depolarized membrane is necessary and sufficient (when the co-agonist glycine is present) to gate the channel. Pairing synaptic stimulation with membrane depolarization provided via the recording electrode (plus the low levels of glycine always normally present) opens the NMDA receptor channel and leads to the induction of LTP.

How is it that the NMDA receptor triggers LTP? The NMDA receptor is a calcium channel, and its gating leads to elevated intra-cellular calcium in the postsynaptic neuron. We will return to this calcium influx that triggers LTP in the next chapter, and indeed most of the rest of this book deals with the various processes this calcium influx triggers.1

These properties, glutamate dependence and voltage-dependence, of the NMDA receptor allow it to function as a coincidence detector. This is a critical aspect of NMDA receptor regulation and allows for a unique contribution of the NMDA receptor to information processing at the molecular level. Using the NMDA receptor, the neuron can trigger a unique event, calcium influx, specifically when a particular synapse is both active presynaptically (glutamate is present in the synapse) and postsynap-tically (when the membrane is depolarized).

!It is important to remember that it is not necessarily the case that every calcium molecule involved in LTP induction actually comes through the NMDA receptor. Calcium influx through membrane calcium channels and calcium released from intracellular stores may also be involved. In fact, it is an interesting "thought experiment" to try to design a way to test this idea—as a practical matter it is much more difficult to determine than one might first think.) Mechanistically the gating of the NMDA receptor/channel involves a voltage-dependent Mg2+ block of the channel pore. Depolarization of the membrane in which the NMDA receptor resides is necessary to drive the divalent Mg cation out of the pore, which then allows calcium ions to flow through. Thus, the simultaneous occurrence of both glutamate in the synapse and a depolarized postsynaptic membrane is necessary to open the channel and allow LTP-triggering calcium into the postsynaptic cell.

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