Ltp Can Include An Increased Ap Firing Component

Another caveat to keep in mind is that the preceding discussion deals only with mechanisms contributing to increases in synaptic strength. The increased EPSP is typically measured in field recording experiments as an increase in the initial slope of the EPSP (or EPSP magnitude), as was discussed in the previous chapter. A second component of LTP is referred to as EPSP-spike (E-S) potentiation. E-S potentia-tion was identified by Bliss and Lomo in the first published report of LTP (11) and is defined as an increase in population spike amplitude that cannot be attributed to an increase in synaptic transmission (i.e., initial EPSP slope in field recordings). Thus, E-S potentiation is a term used to refer to the postsynaptic cell having an increased probability of firing an action potential at a constant strength of synaptic input.

E-S potentiation at Schaffer-collateral synapses can be observed using recordings in stratum pyramidale, as illustrated in Figure 2. In this example Eric Roberson in my lab generated input-output curves for the initial slope of the EPSP and the population spike amplitude, using various stimulus intensities, before and after LTP induction. E-S potentiation is manifest as an increase in population spike amplitude even when responses are normalized to EPSP slope. I should note that we have found that the probability of induction and magnitude of E-S potentiation in area CA1 is more variable than LTP of synaptic transmission. A similar greater variability in E-S potentiation was also observed by Bliss and Lomo in their original report.

FIGURE 2 E-S potentiation in area CA1. Extracellular recordings were made in the cell body layer of area CA1 (using stimulation of the Schaffer-collateral inputs), and input-output curves were performed using a range of 5-45 ^A constant current stimulation. Initial slopes of the EPSP and population spike (PS) amplitude were then determined from the tracings, and the data were plotted as population spike amplitude versus EPSP slope. (A) Superimposed representative tracings for before and 75 minutes after tetanic stimulation, show the increased population spike amplitude after tetanic stimulation. (B) Plots are shown for pre-tetanus (triangles) and 75 minutes post-tetanus (circles). In this experiment, five 100-Hz tetani were delivered. E-S coupling was assayed in hippocampal slices by taking a second set of input-output measurements after the induction of LTP. The baseline I/O curve and the post-stimulation I/O curve were then compared to assess whether a change in excitability had occurred over the course of the experiment. Although we measured both EPSP slope and population spike amplitude from the same waveform recorded from the cell body layer, the preferred approach is to record EPSPs in the dendritic region and simultaneously record spikes independently from the cell body layer. This approach minimizes cross-contamination of the pop spike in the EPSP measurements, and vice versa. Data and figure courtesy of Erik Roberson.

EPSP Slope, mV/ms

FIGURE 2 E-S potentiation in area CA1. Extracellular recordings were made in the cell body layer of area CA1 (using stimulation of the Schaffer-collateral inputs), and input-output curves were performed using a range of 5-45 ^A constant current stimulation. Initial slopes of the EPSP and population spike (PS) amplitude were then determined from the tracings, and the data were plotted as population spike amplitude versus EPSP slope. (A) Superimposed representative tracings for before and 75 minutes after tetanic stimulation, show the increased population spike amplitude after tetanic stimulation. (B) Plots are shown for pre-tetanus (triangles) and 75 minutes post-tetanus (circles). In this experiment, five 100-Hz tetani were delivered. E-S coupling was assayed in hippocampal slices by taking a second set of input-output measurements after the induction of LTP. The baseline I/O curve and the post-stimulation I/O curve were then compared to assess whether a change in excitability had occurred over the course of the experiment. Although we measured both EPSP slope and population spike amplitude from the same waveform recorded from the cell body layer, the preferred approach is to record EPSPs in the dendritic region and simultaneously record spikes independently from the cell body layer. This approach minimizes cross-contamination of the pop spike in the EPSP measurements, and vice versa. Data and figure courtesy of Erik Roberson.

What is the mechanism for this long-term increase in the likelihood of firing an action potential? One possibility that comes to mind is that there could be changes in the intrinsic excitability of the postsynaptic neuron. Particularly appealing is the idea that long-term down-regulation of dendritic potassium channel function could cause a persisting increase in cellular excitability and action potential firing. While investigations of this hypothesis are still at an early stage, some recent work has suggested that E-S potentiation has a component that is the result of intrinsic changes in the postsynaptic neuron.

Progress in testing this hypothesis has been slow owing to the technically difficult nature of the experiments. Most patch-clamp physiologic studies of LTP have utilized recordings from the cell body, which are not capable of detecting changes in channels localized to the dendrites due to technical limitations. Thus, testing the idea of changes in dendritic excitability as a mechanism contributing to E-S potentiation requires dendritic patch-clamp recording, which at present only a few laboratories do routinely.

However, a more thoroughly investigated mechanism for E-S potentiation is based on alterations in feed-forward inhibitory connections onto pyramidal neurons in area CA1 (see Figure 3). A number of different types of neurons in the hippocampus are called interneurons (or intrinsic neurons) because their inputs and outputs are restricted to local areas of the hippocampus

FIGURE 3 The GABAergic interneuron model of E-S potentiation. One potential mechanism for E-S potentiation is diminution of inhibitory feed-forward inhibition through GABA-ergic interneurons in area CA1. Specific possible sites for this effect include LTD of the Schaffer-collateral inputs onto GABAergic neurons or synaptic depression of the interneuron-CA1 pyramidal neuron synapse.

FIGURE 3 The GABAergic interneuron model of E-S potentiation. One potential mechanism for E-S potentiation is diminution of inhibitory feed-forward inhibition through GABA-ergic interneurons in area CA1. Specific possible sites for this effect include LTD of the Schaffer-collateral inputs onto GABAergic neurons or synaptic depression of the interneuron-CA1 pyramidal neuron synapse.

itself (see reference 12). In other words, they only communicate with other neurons nearby in the hippocampus. Most of these neurons in area CA1 use the inhibitory neurotransmitter GABA, and their actions are to inhibit firing of CA1 pyramidal neurons. Different GABAergic interneurons make connections in all the dendritic regions of CA1 pyramidal neurons as well as the initial segment of the axon where the action potential originates. A single GABAergic interneuron may contact a thousand pyramidal neurons; thus, the effects of altered interneuron function are not generally limited to a single follower cell.

Interneurons in area CA1 receive gluta-matergic Schaffer-collateral projections just as the pyramidal neurons do; in fact, the inputs to the interneurons are branches of the same axons impinging the pyramidal neurons. Glutamate release at these interneu-ron synapses activates the interneurons and causes downstream release of GABA onto the pyramidal neurons. This inhibitory action is, of course, slightly delayed at the level of the single cell that receives input from the same Schaffer-collateral axon that is activating the GABAergic interneuron because there is an extra synaptic connection involved.

How does this local circuit contribute to E-S potentiation? Two different groups have shown that the same stimulation that produces LTP at the Schaffer collateral-pyramidal neuron synapses simultaneously produces a decreased efficacy of coupling (long-term depression, LTD) of the Schaffer collateral-interneuron synapses (13, 14). Thus, while the excitatory input to the pyramidal neuron is being enhanced, the feed-forward inhibitory GABA input is diminished. This causes a net increase in excitability and increased likelihood of firing an action potential, added on top of the increased EPSP resulting from the normal LTP mechanisms. This is, of course, the definition of E-S potentiation.

There are a couple of interesting properties for this LTD at the Schaffer collateral-interneuron synapse. First, it is NMDA-receptor-dependent just like LTP. This explains why one does not see E-S potentiation independent of synaptic potentiation in experiments where APV is infused onto the slice. Second, and more interesting, the LTD is not specific to the activated synapse—other Schaffer-collateral inputs onto the same interneuron are also depressed (13). Therefore, there is decreased feed-forward inhibition across all the inputs (and outputs of course) for the whole interneuron. The interneuron has a diminished response to all its inputs, and therefore decreased feed-forward inhibition to all its outputs. Thus, the interneuron LTD appears to be serving to modulate the behavior of an entire small local circuit of neuronal connections. The precise role this interesting attribute plays in hippocampal information processing is unclear at present, but it is under study.

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