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This is solution to assignment which was given at University of Lucknow by Dr. Anurati Shah for Pathophysiology course. It includes: Text, Glutamate, Epsc, Ampar, Current, Desensitization, Nmdar, Depolarized, Excitatory, Postsynaptic
Typology: Exercises
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HST 131/ Neuro 200 18 September 05 Problem Set 3 - Answers Explanation in text below graphs.
20 ms
+40mV
-70mV
AMPAR Current (solid)
AMPAR Current w/ TBOA (assuming no desensitization)
AMPAR Current w/ TBOA (assuming desensitization) (dash)
10 ms
V(pre)
[Glutamate]
EPSC=I(post)
EPSP=V(post)
Time (milliseconds)
Now consider NMDAR only:
20 ms
-70mV
+40m V
NMDAR only - no current unless depolarized
10 ms
V(pre)
[Glutamate]
EPSC=I(post)
EPSP=V(post)
Time (milliseconds)
Timing:
-The presynaptic action potential takes less than 1 ms at mammalian temperatures.
-The entry of Ca ++^ is delayed by about 100 μs (can be as short at 60μs), and is also about 0.5 ms in duration. Although Ca ++^ concentration in the presynaptic terminal as a whole stays somewhat elevated for a while, the concentration near the Ca++^ channels, that is, at the vesicle release site, is high for less than 1 ms, and during that time the vesicles available for release fuse and dump their contents.
-Glutamate increases in the cleft very rapidly (200 μs delay time or more for a monosynaptic delay). Then glutamate rapidly diffuses away or is taken up by glutamate transporters. In the illustration for TBOA, glutamate reuptake by glutamate transporters is blocked, and all removal is due to diffusion.
-The excitatory postsynaptic current rises once AMPA receptors (AMPARs) bind glutamate. AMPARs turn on and off faster than NMDARs, accounting for the short transient. We show the current as negative (inward) since the postsynaptic cell will be resting at -70mV. AMPAR current will roughly follow the glutamate in the cleft, and so lengthening of the current will be observed under conditions (such as TBOA) that keep glutamate around longer. In addition, AMPARs desensitize (close in the presence of agonist) and so postsynaptic current (epsc) is reduced below what might be expected if the glutamate concentration were the sole determinant of current. AMPAR actually desensitize to a relatively large extent, such that the effect of extending glutamate exposure does not greatly increase the amount of synaptic current (think of Dr. Schwarz’s lecture on the Flip and Flop variants of AMPAR and the current timecourse). Desensitization makes this part of the question quite tough. AMPAR currents can decay with a time constant (τ) as rapid as 2 milliseconds, while NMDAR currents can decay much more slowly (τ = 50-200 ms)
-The excitatory postsynaptic potential (epsp) reflects changes due to the synaptic current, with a lag inserted to account for capacitance. In this example, we do not show an active response (firing of an action potential), though we do show the effect of leak currents. (Without any leak, the cell would not sit at -70mV, nor would it return there after excitation.) TBOA also lengthens the epsp, even with AMPAR desensitization.
When we assume that there are only NMDAR receptors, there is no postsynaptic current unless the cell is already depolarized. This is due to the voltage-dependent magnesium block discussed in lecture. With no epsc, there is also no epsp.
Consider the situation with AMPARs and NMDARs: Current through AMPARs flows as before, depolarizing the postsynaptic cell and now allowing current to flow through the NMDARs. This current is larger (NMDAR have larger conductance, and we assume here a similar number of channels) and lasts longer (slower decay τ).
2a) 2b)
For 2b, assume the rise time is fast and that current decays with the slow (P0) or fast time course given in the question. The peak current at various voltages is determined by reference to 2a.
2c) At P0, the GABA current has an amplitude of ~-6 nA at -50 mV membrane potential. (Excitatory, Depolarizing). (Solve I=g(Vm-Vrev ) for the appropriate reversal potential and conductance.)
At P28, the GABA current has an amplitude of ~+1.4 nA (Inhibitory, Hyperpolarizing)
2d) At P0: At P28:
2 2
2
70 25. 4 ln
i
GABA
x mM Cl
x
mV
E mV
1 1
1 120 [ ]
0 25. 4 ln
i
GABA
x mM Cl
x
mV
E mV
Possible mechanisms for accounting for the change in internal concentrations: -A Cl- influx pump @ P -downregulation of the Cl- influx pump, upregulation of a Cl- efflux pump during development. The negative internal charge is primarily made up by membrane-impermeant organic anions at later points in development.
