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(write your name on every sheet) Exam I, Sept 29, 2004
There are 23 questions. Point values for each are given. 86 points total.
- (5 pts) It is important to have a sense for the relative orders of magnitude of cellular components. Circle the answer which is closest to correct for each physical parameter for a CNS synapse.
- (2.5 pts) Indicate which of the following are true. a. Microtubules possess great tensile strength that enables axons to withstand mechanical stress. b. The initial segment and nodes of Ranvier are enormously enriched in delayed rectifier potassium channels. c. The speed of slow axonal transport is only one order of magnitude faster than simple diffusion. d. Presynaptic proteins are often synthesized in the axonal terminal, while dendritic proteins are exclusively made in the soma. e. Dendritic spines are generally thought to constitute the site of long-term, stable memory in CNS neurons.
synapse width (length of active zone)
5 nm 50 nm 500 nm 5000 nm
Lipid bilayer thickness .05 nm .5 nm 5 nm 50 nm
Vesicles released per active zone per action potential 1 10 100 1000
Synaptic delay (pre AP to post AP) 0.1 ms 1 ms 10 ms 100 ms
Synaptic cleft width 0.2 nm 2 nm 20 nm 200 nm
glutamate molecules/ vesicle 50 500 5,000 50,
resting [Ca 2+^ ] in terminal 0.1 μM 1 μM 10 μM 100 μM
[Ca2+^ ] near vesicle for release 0.5 μM 5 μM 50 μM 500 μM
AMPA receptor protein diameter 1 nm 10 nm 100 nm 1000 nm
(write your name on every sheet) Exam I, Sept 29, 2004
3.a. (3.5 pts) Label the following diagram:
b. (2.5 pts) Which one of the above structures is best known to i. trigger action potentials? ii. contain microtubules that are mostly oriented in the same direction? iii. contain microtubules that are of mixed orientation? iv. contain Nissl substance? v. be a site of protein synthesis?
- (3 pts) Myelin... (circle all that apply) a. is made by oligodendrocytes cells in peripheral sensory nerves b. decreases the effective capacitance of an axon c. decreases the length constant of an axon d. decreases the effective resistance of an axonal membrane e. is lost in the disease myaesthenia gravis f. increases conduction velocity to 20-100 mm/s
- (2.5 pts) A typical mammalian CNS synapse differs from the neuromuscular junction (NMJ) in the following ways (circle all that apply): a. A CNS presynaptic terminal typically releases 1 vesicle per action potential while a NMJ terminal releases hundreds. b. Acetylcholine is hydrolyzed by acetylcholinesterase in the cleft at the NMJ, while glutamate is cleaved by glutamate hydrolase in the cleft in CNS synapses. c. NMJ synapses have dense-core vesicles while CNS vesicles are usually clear. d. CNS, but not NMJ presynaptic terminals can be postsynaptic to inhibitory neurons. e. A muscle cell is innervated by a single motor neuron while a CNS neuron can be postsynaptic to many neurons.
(write your name on every sheet) Exam I, Sept 29, 2004
- One channel type that we did not dwell on is the A-type potassium channel, which activates much like other delayed rectifier channels but which inactivates fairly rapidly. Suppose an A-channel in a particular cell has the following voltage dependencies of activation and inactivation (left) and the following open-channel I(V) curve for a single channel (right). Suppose also that at –50mV, the A-current activates with a τ of 0.5ms and inactivates with a τ of 15ms.
0
1 Activation
-100 -80 -60 -40 -20 (^0) mV
P(open)
gates
Inactivation gates
0
1
2
3
-100 -80 -60 -40 (^) mV -
pA
a. (4 pts) With a patch clamp, you record from a SINGLE A-type potassium channel, holding at –80mV and stepping to –50mV for 10ms. Draw a typical record for the current through a single channel.
0
1
2
si ngl e channel c urrent (pA) -80mV
-50mV
(write your name on every sheet) Exam I, Sept 29, 2004
10b. (4 pts) After blocking all other channels, you record from the WHOLE-CELL, holding at –80mV and pulsing to –50mV for 10ms. Assuming your cell has ~1000 A- type K+ channels, draw the expected current, indicating an appropriate current scale.
c u
rre n t
(p A)
-8 0m V
-5 0m V
c. (2 pts) To see the effect of the A-type channels on the cell’s action potential, you pass current (not in voltage clamp) to stimulate an action potential. If the action potential shown below is in the absence of the A channels, draw what you would expect to happen when they are present.
0
20
40
membrane potential (mV)
- (4 pts) For a standard voltage-gated potassium channel that has inactivation, which part(s) of the protein correspond to each of these functions? a. the voltage sensor
b. the selectivity filter
c. the activation gate
d. fast inactivation
(write your name on every sheet) Exam I, Sept 29, 2004
t tamatergic
at the ive
ay).
. (2 pts) What is the likely target of Drug A? . (2 pts) Why does Drug A have little or no effect at a . (1 pts) You decide to do the experiment one more time (just to be sure), but realize
t –
12.d. (3 pts) Assume all inputs have ionotropic glutamate receptors except for input C, which is a GABAergic synapse dominated by GABAA receptors. You study the effect of input C on inputs B and D. Although input D is electrotonically closer to input C, you find that input C has a greater inhibitory effect on input B. Why?
- You voltage clamp a hippocampal pyramidal cell a various holding potentials, stimulate its glu input fibers and observe the following EPSCs in response (drawn in black.) You are surprised th time course is quite different at positive and negat holding potentials. When you add Drug A, the time course becomes much more consistent (drawn in gr
a
b holding potential of –80 mV?
c right before that you have run out of external solution for your experiment. You hurriedly make up a new batch. This time, however, you’re surprised to see that a mV the EPSC now has a long, slow time course similar to that seen at +20 mV. Furthermore, addition of Drug A makes the EPSC at –80 mV quick again, as in Experiment 1. What ion did you forget to add to your solution?
EXPERIMENT 1
Drug A
Drug A
100 pA 50 ms
(write your name on every sheet) Exam I, Sept 29, 2004
- (2.5 pts) Which of the following is true about transmission of EPSPs along dendrites. a. EPSPs become smaller in amplitude and shorter in duration as they move along passive dendrites
ecrease
- (2.5 pts) al down an ax a. increasing axon diam
velocity by decreasing Rm le node
by cetylcholine or m rrent.
ntials
b. Potentials travel more readily away from the soma than towards it c. Inhibitory inputs shunt EPSPs more readily when then are near the cell body than when they are in distal dendrites d. At dendritic branch points the length constant can either increase, d or stay the same e. EPSPs from distal dendrites are often larger than expected from passive propagation both because synapses are stronger at distal locations and because they can stimulate action potentials in the dendrites
Which of the following are true about the propagation of the action potenti on (circle all that apply): eter speeds up propagation b. increase the number of K+ leak channels speeds up propagation c. increasing the number of voltage-gated Na+ channels speeds up propagation d. the myelin sheath primarily increases propagation e. because conduction between nodes is saltatory, eliminating a sing of Ranvier would abolish propagation along the axon
- (2 pts) There is potassium channel made of KCNQ2 and KCNQ3 subunits, whic h is partly open at rest, and slowly opens more when depolarized. This channel is closed a uscarine, and so current through this channel is called the M-cu Which are likely to be true about the M-current? a. acetylcholine probably acts on the current through a second messenger b. application of acetylcholine to dendrites containing KCNQ2/3 will increase the length constant of the dendrite c. cells with KCNQ2/3 will have a harder time firing a burst of action pote than a single action potential d. application of acetylcholine to a presynaptic terminal containing KCNQ2/3 will decrease vesicle release
(write your name on every sheet) Exam I, Sept 29, 2004
- (2 pts) You have spent years to identify the gene for a rare, dominantly inherited paralytic disease. The disease is characterized by a temporary inability to generate action potentials in the muscle after heavy exercise. The gene you finally identify encodes an inwardly rectifying potassium channel, and the disease is correlated with a single amino acid change in its selectivity filter. Experiments on mutant channels expressed in cultured cells indicate that the channel becomes less selective for K+^ when lactic acid builds up and the residue is protonated. What is the single most likely etiology for the disease? a. Na +^ influx depolarizes the muscle to a region where voltage-gated Na+^ channels are largely inactivated. b. Because the channel is less K+^ -selective, K+^ leaks into the muscle, shifting the K+^ Nernst potential more negative and hyperpolarizing the cell c. Ca 2+^ influx stimulates continuous neurotransmitter release, and desensitization of nACh receptors d. K+^ accumulation in the T-tubules depolarizes the muscle cells
- (6 pts) Execution by lethal injection involves administration of the following drugs, in order: sodium thiopental (a barbiturate), tubocurarine chloride (a.k.a. curare), and potassium chloride. For each, indicate the important molecular target, and the effect on the inmate.
sodium thiopental target:
effect:
tubocurarine chloride target:
effect:
potassium chloride target:
effect:
- (3 pts) What are three widely used treatments for epilepsy?
(write your name on every sheet) Exam I, Sept 29, 2004
- (4 pts) Bipolar disorder is often treated with drugs such as Prozac, Celexa, Zoloft, and imipramine. While they apparently target synapses, an unusual feature of them is that they don’t have much effect for the first 2-3 weeks.
a. What synaptic process or molecule is thought to be their target?
b. What new hypothesis for their action would explain the delay in efficacy?
