Synaptic Transmission [6]

Question 1

The mechanism of the action potential and the Nernst equation.

Answer 1

x

Question 2

What is electrical synaptic transmission? Name a limitation of this form of intercellular communication (compared to chemical transmission)

Answer 2

Electrical synaptic transmission occurs when electrical current is spread from one neuron to another via gap junctions between cells.

The problem with electrical synaptic transmission is that it cannot provide the same amplification of signal that chemical synaptic transmission can achieve.

Also can only be excitatory, and integration of signals is difficult

Question 3

Why would electrical synaptic transmission be ineffective at the neuromuscular junction? Is this method of communication important in the mammalian CNS?

Answer 3

For electrical synaptic transmission to work, e.g. provide enough current to depolarize the post-synaptic cell to threshold, the pre- and post- synaptic cells need to be comparable in size. In the NMJ, the presynaptic nerve terminal is dramatically smaller than the postsynaptic muscle fiber it innervates. It could never provide enough current to depolarize the muscle (by 30mV) using electrical synaptic transmission. The NMJ works because of a chemical amplifier

Question 4

Name examples of electrical synaptic transmission.

Answer 4

• escape reflexes in animal kingdom,
• synchronously firing networks
• heart muscle contraction
• Development of retina, inner ear
• CNS: fear learning, emotional memory in hippocampus
• Contribution to the establishment of (alert) theta rhythms

Question 5

Name the presynaptic events involved in transmitter release, from the time of the arrival of an action potential to exocytosis

Answer 5

AP arrives at motor nerve terminal (presynaptic cell) → voltage gated Ca+2 channels open → influx of Ca+2 → fusion of vesicle membrane with nerve terminal membrane → synaptic vesicle exocytosis → ACh released into the synaptic cleft.

ACh binds to *ACh Receptors in postsynaptic cell (muscle fiber) → ligand-gated ion channels open → Na+ (and other cations) flow into the muscle fiber → muscle fiber depolarizes to threshold → voltage-gated ion channels open → even more Na+ enters the cells → 2 APs generated, travel in opposite directions to reach each tendon

*ACh Receptor is a Non-Selective Cation Channel

Question 6

Describe the subsequent presynaptic events involved in cleanup operations, both outside the cell (consider the neurotransmitter molecules) and inside the cell
(consider sodium ions, calcium ions, synaptic vesicles, and neurotransmitter)

Answer 6

1. Pre-synaptic Cell:
   • Ca2+ ions pumped back out of the nerve terminal
   • Post-exocytic synaptic vesicles are retrieved by “kiss-and-run” vesicles (after single action potential) or by full fusion exocytosis (after prolonged stimulation)
2. Synaptic Cleft: Get rid of excess ACh through simple diffusion, ACh Esterase (most important!) or Reuptake
3. Post-synaptic Cell:
   • Muscle fiber must extrude the Na+ and Ca2+ ions that entered through ACh-gated channels
   • Must also reabsorb K+ ions lost through the same pathway
   • Uses Na+/K+ pump and Ca2+ pump located in the cell membrane

Question 7

How does tetanus toxin act, how does botulinum toxin act?

Answer 7

Botulinum toxin cleaves SNAREs on

Tenanus toxin also acts on

Question 8

Name the postsynaptic events involved in synaptic transmission.

Answer 8

• Muscle fiber must extrude the Na+ and Ca2+ ions that entered through ACh-gated channels
• Must also reabsorb K+ ions lost through the same pathway
• Uses Na+/K+ pump and Ca2+ pump located in the cell membrane

Question 9

What is the ‘job description’ for a motor nerve terminal?

Answer 9

Every time an AP arrives from the CNS, you must secrete enough ACh to depolarize the muscle fiber you innervate to threshold for an AP (about 30 mV).
• If you secrete 1 molecule of ACh too little → muscle will not initiate an AP and you’ll get no twitching at all
• If you secrete buckets of ACh → muscle fiber will still only give a single twitch and you’ll have wasted a lot of ACh
Thus, the neuromuscular synapse acts as an all-or-none switch.

Question 10

Describe how the neuromuscular synapse amplifies the incoming signal in order to depolarize the muscle fiber to threshold for an action potential.

Answer 10

Need to depolarize by 30mV (-80mV to -50mV):

1 Vesicle = 2000 molecules of ACh+

2 ACh+ to activate each ACh Receptor = 1000 ACh Receptors that can be activated per Vesicle

1nV per ACh+ → 1000 ACh+ x 1nV = 1uM

1uM x 1000 ACh Receptors = 1mV of depolarization per Vesicle

1mV per Vesicle x 100 Vesicles = 100mV = Depolarization

Question 11

What is the safety factor at the neuromuscular junction? Do CNS synapses have safety factors as well? Why / why not?

Answer 11

The motor nerve terminal secretes the contents of a few times more than the minimum number of
synaptic vesicles needed. This safety factor comes in handy during repetitive stimulation, when
the number of vesicles that undergo exocytosis with each stimulus declines

The CNS doesn’t really have a safety factor

Question 12

When would you see facilitation and synaptic depression?

Answer 12

Both facilitation and synaptic depression occur during repetitive stimulation.

Depression: Reduction of the number of available vesicles during periods of high-frequency activity. Time course: seconds to about 1 minute.

Facilitation: Accumulation of calcium in the presynaptic terminal. Time course: milliseconds to

Question 13

Describe the basic mechanism that determines whether a synapse is direct (fast) or indirect (slow). Name a typical physiological response mediated by each.

Answer 13

Fast Synapse: Ionotropic (NT directly gates an ion channel)
• Example: Muscle Fiber Depolarization
o ACh binds to nicotinic AChR → opens NSC Channel → Na+ flows in → muscle fiber depolarizes

Slow Synapse: Metabotrophic (NT gates a G-Protein Coupled Receptor and requires the activation of a second messenger)
• Example: Opening K+ channels in the heart
o ACh binds to muscarinic AChR → Activates GPCR → γβ Subunit is released and diffuses to the K+ channel → γβ Subunit binds and opens the K+ channel → K+ exits the cell

Question 14

Describe the conductance (permeability) characteristics of the channel opened in fast excitation. Define the electrical “driving force.” Define the reversal potential for direct excitation.

Answer 14

x

Question 15

Describe the kind of channel that is opened during fast inhibition in the CNS

Answer 15

Fast synaptic inhibition (often through GABA) acts by opening chloride channels in the post-synaptic membrane. The chloride equilibrium potential is more negative than the threshold potential (it is more negative than some resting membrane potentials) so chloride moving into the cell does not result in an action potential

Question 16

Why is inhibition often more powerful than one might predict from the size of an individual inhibitory post-synaptic potential (IPSP)?

Answer 16

Membrane potential is determined by the relative permeability of all the participating ions, not the individual amplitudes of the excitatory or inhibitory post-synaptic potentials. A small inhibitory post-synaptic potential can reflect a very large change in ion permeability if the ion’s equilibrium potential is close to the resting membrane potential (i.e. chloride potential)

Question 17

Define temporal and spatial summation of postsynaptic potentials.

Answer 17

When two presynaptic inputs both synapse on a single neuron, their potentials can be added together and form a larger potential as a significant increase in neurotransmitter is released. If a single input is stimulated twice in succession, the second rise in potential can start rising before the previous action potential has ended. The amplitude of the potentials will summate algebraically to create a potential that is larger than the individual potentials.

Question 18

Describe the three mechanisms for removing transmitters from synaptic clefts.

Answer 18

1. Diffusion: This is common in both the CNS and at the NMJ. Small molecules can diffuse into the large amount of extracellular fluid that is adjacent and contiguous with the synaptic cleft.
2. Reuptake: There are many neurotransmitter specific pumps in the presynaptic terminal (NMJ, where reuptake is less important) or the surrounding glia (CNS, reuptake is very important). These pumps move neurotransmitter from the synapse into the cell and then the neurotransmitters must be returned to synaptic vesicles.
3. Destruction: This pathway is common at the NMJ for acetylcholine, but rare in the CNS. Acetylcholine esterase is an enzyme that resides in the synaptic cleft and breaks ACh down into choline and acetate, which are not effective transmitters. The choline can then be pumped into the cell and converted back to ACh.

Question 19

What is a coincidence detector?

Answer 19

a process by which a neuron or a neural circuit can encode information by detecting the occurrence of temporally close but spatially distributed input signals.

Question 20

What is LTP, what is LTD? How are they involved in learning and memory?

Answer 20

Long-Term Potentiation: LTP
An increase in the synaptic current produced by a synapse after a pairing event.

Long-Term Depression: LTD
A decrease in the synaptic current produced by a synapse after a pairing event.

If you learn anything, the learning happens at the synapses, and is “stored” there. Stronger synapses = LTP = better memory
LTP can neutralize the LTD and vis versa- you can learn and unlearn things!

Question 21

Define and describe the mechanism of Facilitation

Answer 21

Facilitation is due to the residual calcium inside the nerve terminal, left over from previous action potentials that has not yet been able to be pumped out of the cytoplasm
due to stimulation frequency.

Question 22

Define and describe the mechanism of Synaptic Depression

Answer 22

During repetitive stimulation, the nerve terminal starts to run out of releasable vesicles: it can’t replenish the synaptic vesicles from its reserves fast enough to keep up with demand. As a result, the number of quanta released during each synaptic potential will decrease.

Synaptic depression is due to depletion of releasable synaptic vesicles

Question 23

How does the NMDA receptor work as a coincidence detector?

Answer 23

The NMDA receptor requires two separate signals occur simultaneously in order to conduct and thus is a coincidence detector. Glutamate released from the presynaptic cell must bind the channel and a post-synaptic action potential must depolarize the membrane enough to electrically force the Mg out of the pore. This allows calcium to influx into the cell.
Calcium ions in the post-synaptic cell strengthen the synapse by causing the insertion of additional AMPA receptors into the post-synaptic membrane. Increased AMPA receptors allow the neuron to respond more strongly to the same amount of released neurotransmitter.

Question 24

How can activation of NMDA receptors lead to synaptic strengthening? How might such a mechanism lead to behavioral associative conditioning?

Answer 24

When NMDA receptors are activated and calcium flows into the cell, the cell is stimulated to make NO, which then diffuses backwards across the synapse. The presence of NO potentiates neurotransmitter release, i.e. the pre-synaptic cell secretes more quanta of transmitter.

This mechanism can be used to develop behavioral associative conditioning by pairing conditioned and unconditioned responses together (think Pavlov’s dogs, ring a bell and salivate). The weak synapses can be strengthened by pairing the bell (weak input) and meat (strong input). The key to pairing is coincidence.

Question 25

Name the 11 steps of an excitatory chemical synapse that you should know by now

Answer 25

1. Action potential travels along axon and arrives at synaptic terminal (presynaptic side).
2. Presynaptic terminal depolarizes.
3. Voltage gated calcium channels open.
4. Calcium diffuses into terminal.
5. Calcium triggers fusion of vesicles with presynaptic membrane.
6. Exocytosis.
7. Transmitter diffuses across synaptic cleft.
8. Transmitter binds to receptors at postsynaptic side (dendrite).
9. Receptors open and allow positive ions to enter cell.
10. Depolarization, EPSP.
11. If threshold is reached, action potential in postsynaptic cell is elicited.

Question 26

What is the neurotransmitter of the neuromuscular junction?

Answer 26

Acetylcholine

Question 27

What are the neurotransmitters of the CNS?

Answer 27

Glutamate (+), glycine (-), GABA (-)

Question 28

Myasthenia gravis

Answer 28

Antibodies to postsynaptic acetylcholine receptors. Patients are weak and become weaker with exercise

Question 29

Myasthenic syndrome

Answer 29

Antibodies to presynaptic calcium channels. Patients are weak and become stronger with exercise.