Question 1: Currents in the VTA projection neuron (60pt)
Scientists wanted to understand how VTA projection neurons (see the diagram from the beginning of question 3) react to drugs of abuse. In particular, they wanted to know if VTA projection neurons would respond any differently to glutamatergic inputs before and after exposure to drugs of abuse. This is their paper:

Saal et al. 2003. Drugs of Abuse and Stress Trigger a Common Synaptic Adaptation in Dopamine Neurons. Neuron 37: 577.

4.1 Summation at 40mV (12pt)
In the paper, the researchers measured iGluR currents when cells were clamped at 40mV. Imagine that a VTA projection neuron in vivo is somehow already at 40mV and then receives some glutamate. It has not been given drugs. According to the currents seen in Figure 1B, which would be better able to participate in temporal summing that would lead to an action potential: a glutamatergic EPSC that arose from only the cell’s NMDARs or a glutamatergic EPSC that arose from only the cell’s AMPARs? What about for spatial summing? Justify your response. (roughly 2-3 sentences)

4.2 Summation at rest (12pt)
Now imagine the VTA projection neuron in vivo at its resting membrane potential. Again, it receives glutamate but not drugs. Which would be better able to participate in temporal summing that would lead to an action potential: a glutamatergic EPSC that arose from only the cell’s NMDARs or a glutamatergic EPSC that arose from only the cell’s AMPARs? What about for spatial summing? Justify your response. (roughly 2-3 sentence)

4.3 Drugs (12pt)
Say that Model 1 is that drugs of abuse make the VTA projection neuron more likely to fire from glutamatergic input, and Model 2 is that drugs of abuse make the VTA projection neuron less likely to fire from glutamatergic input. Which model do Figures 1 and 2 support? Justify your response. (roughly 2-3 sentences)

4.4 Hypotheses (14pt)
Which of these hypotheses might plausibly cause the same kind of change in AMPAR/NMDAR EPSC ratio after drug administration that is seen in this paper? In your justification, address each of the hypotheses. (roughly 1-2 sentences per hypothesis)

a. More AMPARs are inserted into the membrane after giving drugs
b. β-arrestin causes NMDARs to be internalized after giving drugs
c. Conductance through the AMPARs increases after giving drugs
4.5 Nicotine (10pt)

Another paper replicated the results seen in Figure 2B with nicotine. They did further experiments to conclude that the change nicotine causes in AMPAR/NMDAR EPSC ratio was due to the effect of nAChRs present on the VTA projection neuron itself. Is this change in the AMPAR/NMDAR EPSC ratio likely to be a direct result of signaling through the nAChR, or are there likely to be many steps in between signaling through the nAChR and this change in iGluR EPSC ratio? Justify your response. (roughly 1-2 sentences)

Question 1: Currents in the VTA projection neuron (60pt) Scientist...