Temporal Integration In Ltp Induction

At one level, it is a statement of the obvious to say that LTP induction depends on temporal integration. After all, the only thing that distinguishes the LTP induction protocols from baseline stimulation is that, during the LTP induction protocol, stimulation is delivered at a higher rate. It obviously is the case that if the only thing that is different is that the synapse is seeing activity at 100 pulses per second rather than once every 20 seconds, then LTP is being triggered by unique timing-dependent processes, which is simply a restatement of one definition of temporal integration. But what unique events are happening physiologically with high-frequency stimulation? Stated briefly, the answer to this question is that temporal integration is occurring such that the cell is reaching a threshold of depolarization in order to fire an action potential (15-17). This action potential firing then leads to membrane depolarization to allow opening of NMDA receptors. Next I will describe two different ways in which this can happen.

The first mechanism can be illustrated by considering what happens during the 1-second period of 100-Hz tetanus. Such closely spaced stimulation means that postsynaptic depolarization from the first EPSP carries over into the second stimulation, and so on, and so on, 96 more times. Stated more precisely, the postsynaptic membrane potential does not recover to the original resting potential before an additional depolarizing EPSP is triggered, and temporal summation of postsynaptic depolarization occurs. The summed depolarization eventually reaches threshold for the cell to fire an action potential (see Figure 4). This is one of the classic examples of neuronal temporal integration, and, of course, such a process is not limited to hip-pocampal pyramidal neurons. One unique aspect of this in hippocampal neurons, and

Low-Frequency Stimulation

FIGURE 4 Temporal integration in LTP induction. Temporal summation of EPSPs is one mechanism contributing to bringing the postsynaptic neuron to threshold for firing an action potential, one contribution to the selective ability of high-frequency stimulation to produce LTP.

Low-Frequency Stimulation

Time

FIGURE 4 Temporal integration in LTP induction. Temporal summation of EPSPs is one mechanism contributing to bringing the postsynaptic neuron to threshold for firing an action potential, one contribution to the selective ability of high-frequency stimulation to produce LTP.

probably other cortical neurons as well, is that triggering of the action potential is used to generate a back-propagating action potential into the dendrites, which is involved in depolarizing the NMDA receptor and triggering synaptic plasticity.

A second example comes from considering LTP induced by theta-pattern stimulation. With this type of LTP induction protocol, delivered at the slower 5-Hz (once every 200 ms) rate, temporal integration is similarly involved but occurs via a different route. After all, 200 ms is long enough for the postsynaptic membrane potential to recover completely before the next wave of depolarization, so temporal integration of the sort described here is inadequate as an explanation. Joel Selcher in my laboratory investigated this question by examining the physiologic events occurring during the period of theta-frequency stimulation. For illustrative purposes, I will discuss Joel's results with theta-frequency stimulation, although he and others observed similar effects with theta-burst stimulation as well.

For these experiments, Joel used theta-frequency stimulation (TFS) consisting of 30 seconds of 5-Hz stimulation. This stimulation paradigm evokes stable LTP as described earlier and as illustrated in Figure 5. Joel then assessed population spikes during the theta-frequency stimulation period, utilizing a dual-recording electrode technique. The stimulating electrode remained in hippocampal area CA3 and activated Schaffer-collateral fibers innervating area CA1. One recording electrode was positioned in stratum radiatum of area CA1 in order to record synaptic responses, field EPSPs (Figure 5B). Joel placed another electrode in stratum pyramidale, the cell body layer, in order to record action potential firing in response to the same input. For each single stimulus, the initial slope of the EPSP recorded in stratum radiatum and the amplitude of the population spike recorded in stratum pyramidale were measured throughout the period of 5-Hz stimulation.

Theta-frequency stimulation resulted in a short-lived increase in action potential firing during the 30 seconds of 5-Hz stimulation (see Figure 5C, D). For roughly the first 20 seconds of the stimulation, the amplitude of the population spike increased dramatically. Meanwhile, over this same time period, the EPSP slope recorded in stratum radiatum gradually declined. Therefore, the ratio of the population spike amplitude to the EPSP slope increased over time, indicating an increased likelihood of action potential firing over the short time course of the TFS (Figure 5D). Once again, for TFS as for 100-Hz tetanic stimulation, some temporal integration process is taking place to cause action potential firing during the period of LTP-inducing stimulation.

The mechanism for this temporal integration is not clear at present: clearly temporal summation of the sort operating in 100-Hz stimulation is not sufficient to explain it. However, a variety of previous studies have suggested that for LTP induced by TFS there is an important role for attenuation of feed-forward GABAergic inhibition onto pyramidal neurons (see references 18, 19, and 20 and Figure 6). One current hypothesis is that short-term synaptic depression in the GABAergic local circuit during theta-frequency stimulation, which is a result of stimulation of presynaptic GABA-B autoreceptors, leads to a loss of GABA-mediated inhibition, increased excitability, and increased firing of action potentials during the period of theta-frequency stimulation.

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