Synaptic Plasticity III: Design and Analysis of a Plastic Synapse

Analysis

• In the previous units, all features of the synapses have been visible to you, and so it has been straightforward to change a parameter and determine how the model neuron responds.

• If you were studying a nervous system, however, you would need to deduce many of these parameters experimentally.

• Here is the simulation you will be working with during this unit:

• Question 1. Click on the Analysis button. Is the postsynaptic potential excitatory or inhibitory?
  • To confirm that you are correct, please do the following. Set the Number of pulses in the presynaptic neuron to 0, and set the Number of pulses in the postsynaptic neuron to 6. Now reduce the stimulus current injected into the postsynaptic neuron to a minimum value that is just enough to fire the neuron (this is labeled Additional stimulus current during pulse; you should try to get two or three significant figures).
  • Set the Number of pulses in the presynaptic neuron to 6, and change the stimulus current injected into the postsynaptic neuron to a minimum value that is just enough to fire the neuron (again, you should try to get two or three significant figures). Does this result confirm your hypothesis?

• Question 2. Is the synapse plastic, i.e., does the amplitude of the individual post-synaptic potential change after repeated firing, and is it facilitating or depressing? Recall that if the strength of a synapse increases, it is called a facilitating synapse; in contrast, if the strength of the synapse decreases, this is referred to as a depressing synapse.
  • To confirm that you are correct, press the Analysis button to reset the simulation. Change the Total duration of the simulation to 500 ms, change the presynaptic stimulus current to 20 nA (this is labeled Additional stimulus current during pulse), and vary the inter-stimulus interval from 10 ms, to 20 ms, to 50 ms, and finally to 100 ms. What do you observe? Please measure the amplitude of the first two PSPs from their base to their peak, and report the results. Does this result confirm your hypothesis?

• Question 3. What is the reversal potential of the synapse?
  • To answer this question using current clamp, you need to shift the resting potential of the postsynaptic neuron by injecting a continuous current into it, called a bias current. The following instructions will walk you through this process.
  • Press the Analysis button to reset the simulation.
  • Set the Total duration of the simulation to 500 ms.
  • Set the presynaptic neuron current clamp to have a Stimulus delay of 80 ms, a stimulus current of 40 nA (this is labeled Additional stimulus current during pulse), an Inter-stimulus interval of 6 ms, and set the Number of pulses to 10.
  • Set the postsynaptic neuron current clamp to have a Stimulus delay of 0 ms, a Stimulus bias current of 0 nA, an Additional stimulus current during pulse to 0, a Pulse duration of 2 ms, and set the Number of pulses to 1.
  • Run the simulation. What do you observe?
  • Now shift the resting potential of the postsynaptic neuron by injecting steady positive or negative current (you will need to determine which is appropriate) by changing the Stimulus bias current for the postsynaptic current clamp from its initial value of 0 in increments of +1 nA or -1 nA. Once you see a reversal of the postsynaptic potentials (not action potentials!), use binary search to obtain a more precise value of the bias current that creates smaller and smaller postsynaptic potentials around the point of reversal.
  • Determine the current that minimizes the postsynaptic potentials, so that their size is essentially zero (pay attention to the y-axis!). Measure the potential at which this occurs, and confirm that it is the reversal potential by showing that more or less injected Stimulus bias current into the postsynaptic neuron causes the postsynaptic potential to change sign.

• Question 4. Is the synapse due to an increased conductance or a decreased conductance of the postsynaptic membrane?
  • To answer this question using current clamp, first press the Analysis button.
  • In the Presynaptic Current Clamp, set the Stimulus delay to 100 ms, the Stimulus bias current to 0 nA, the Additional stimulus current during pulse to 20 nA, the Pulse duration to 2 ms, the Inter-stimulus interval to 10 ms, and the number of pulses to 24. Set the Total duration of the simulation to 600 ms.
  • In the Postsynaptic Current Clamp, set the Stimulus delay to 10 ms, and the Stimulus bias current to the value that you determined when you answered Question 3. To inject small pulses of additional current into the neuron to see how its conductance changes, set the Additional stimulus current during pulse to -0.01 nA. Set the pulse duration to 5 ms, and the Inter-stimulus interval to 250 ms.
  • To see what the neuron is doing before the small additional negative currents are injected, set the postsynaptic Number of pulses to 0. Run the simulation. What do you observe? Measure the size of the change that you observe in the potential of the postsynaptic neuron from before the presynaptic neuron fires to the last few action potentials in the presynaptic neuron. How large is the voltage change? How much will this change the driving force of the synapse? Explain the reason that a large change in the driving force could make it difficult to measure the conductance change.
  • Now set the number of pulses in the postsynaptic neuron to 3. Run the simulation. What do you observe? Measure the size of the change in the voltage of the postsynaptic neuron during each small inhibitory stimulus pulse. What happens to its size while the synapse is active, as opposed to before or after?
  • Recall that conductance is $g = \Delta I / \Delta V$, and that, in this experiment, you are injecting a fixed amount of current into the neuron.
    • If the voltage change, $\Delta V$, resulting from the small inhibitory stimulus current pulse, $\Delta I$, gets larger during the postsynaptic potential (PSP), has the conductance, $g$, of the postsynaptic membrane increased or decreased?
    • If the voltage change, $\Delta V$, resulting from the small inhibitory stimulus current pulse, $\Delta I$, gets smaller during the postsynaptic potential (PSP), has the conductance, $g$, of the postsynaptic membrane increased or decreased?
  • Based on your measurements, does the postsynaptic potential (PSP) that you are studying result from an increase or decrease in the conductance of the postsynaptic membrane? Explain your reasoning.
  • Based on the reversal potential you found in Question 3 and the change in conductance you found in this question, which ion is most likely responsible for the postsynaptic potential? How would you test your hypothesis? Explain.

Design

• As we saw in the unit on multiple conductances, one way in which nervous systems can generate rhythmic behaviors is to insert multiple ionic conductances into the nerve cell membrane, and as a natural consequence of the interaction of the different currents, the nerve cell can spontaneously generate bursts. You also showed, through your design efforts, that bursters could be made conditional on excitatory input.

• A different way in which nervous systems generate rhythmic behaviors is through synaptic interactions.

• Open the simulation above in a separate window, and press the Design button. Unlike in the Analysis simulation, the postsynaptic neuron now fires spontaneously. We will guide you through the first steps of creating your own rhythmic burster using a synaptic connection.

• Question 5. Increase the pulse duration to 20 ms. What happens? Now change the number of pulses to 2. What happens? Change the inter-stimulus interval to 80 ms. What happens?

• Question 6. Design a pulse protocol to create a continuous series (i.e., more than two) of alternating bursts of two action potentials in the presynaptic and postsynaptic neuron. Find the minimum pulse duration and minimum inter-stimulus interval for doing this (so that your oscillator can burst as rapidly as possible).

• Question 7. Repeat the design process, but now set up a continuous series of alternating oscillations of three action potentials, and then four action potentials, on both the pre- and postsynaptic neurons. Do you observe any pattern in the intervals that you need to use for doing this?