Physiology of Neurons

Question 1

Electrical Synapses

Question 2

What is the clinical importance of measuring conduction velocity?

Answer 2

• This is measured to investigate the source of motor weakness in arms and legs.
• It can detect gross pathological changes such as conduction block and conduction slowing, which could signify demyelination or degeneration.
• It can help diagnose: Peripheral neuropathy, Carpal tunnel syndrome, Spinal disc herniation, etc.

Question 3

Draw a graph of a neural action potential. Include axes (and their labels), units, and approximate numerical values.

Answer 3

Question 4

For each of those phases of the action potential: list the ionic current (and the ion’s direction of movement) that is responsible.

Answer 4

• Resting membrane potential is determined primarily by K+ moving down its concentration gradient (leaking out of cell), leaving behind negative anions inside membrane. This is due to leak and some inward rectifier currents.
• Depolarisation is due to Na+ rapidly coming into the cell.
• The threshold is the voltage above which the cell is committed to completing an action potential. It occurs when inward Na+ current depolarizes the cell faster than outward K+ current can repolarise the cell back to the RMP.
• Repolarisation is due to Na+ channels inactivating while K+ is rapidly leaving the cell via the delayed rectifier channels. It is NOT the Na/K pump, which only changes Vm by 3 mV.
• The afterhyperpolarisation is when Vm is most close to EK at the end of the AP. Many different sources of K+ permeability cause K+ to flow out: inward rectifiers, leak, and delayed rectifiers (which are delayed in their closing). In addition, during the AHP unusually little Na+ is flowing because the Na+ channels are inactivated (which occurs after a delay when Vm is above -40 mV)

Question 5

Name the main transmembrane forces on an ion.

Answer 5

•Chemical (diffusional) and electrical

Question 6

What is a graded potential?

Answer 6

• It is a change in the membrane potential that is NOT an action potential. It can vary in voltage amplitude and in time duration. A graded potential is not amplified, and it is not all-or-none.
• It can occur at receptor cells (eg rods and cones) where it is important in transduction of light/pressure into a graded electrical potential
• Also occurs at synapses.

Question 7

What is a refractory period?

Answer 7

• A refractory period is a time duration after one action potential has just fired when another action potential either cannot (absolute refractory period) is resistant to (relative refractory period) restimulation to begin a new action potential. It often is associated with Vm being lower than the RMP (the after-hyperpolarisation), and it is usually caused by a high permeability to K+ (i.e. more K+ channels are open than at rest).

Question 8

What is an equilibrium potential?

Answer 8

• It is the voltage where the amount of a particular ion (e.g. Na+) flowing out of the cell = the amount of that ion flowing in. It happens when the electrochemical forces for that ion type are in equilibrium.
  
  • E.g. For Na+, this occurs when the diffusion (chemical) forces pushing Na+ into the cell equal the voltage (electrical) forces pushing Na+ out of the cell

Question 9

Draw a diagram showing the two forces on K+ ions at its equilibrium potential.

Answer 9

Question 10

Name the equilibrium potentials for Na+, K+, Ca2+ and Cl¯ (in a typical cell).

Answer 10

• ENa = ~ +55 mV (or you could say +60).
• EK = ~ -90 mV
• ECa = ~ +123 mV
• ECl = ~ -40mV (although this varies by cell type and is sometimes quoted as being -65 mV)

Question 11

Why is the resting membrane potential -70 mV when there are so many positive K+ ions inside the cell?

Answer 11

• Resting membrane potential is determined by which ion has the most conductance. Because at rest K+ is by far the most conducted ion, the high K+ that is leaking out of the cell leaves behind negative ions (esp. proteins and Cl-). The fact that there are so many K+ ions inside the cell does not make the inside positive because virtually every single one of the K+ ions is balanced by a negative charge (proteins & Cl-) right next to it.

Question 12

Give two examples of drug classes that block sodium channels as part of their mechanism of action.

Answer 12

• Local anaesthetics (eg lidocaine). Some anticonvulsants (eg carbamazepine). Type I cardiac antiarrhythmic drugs (eg quinidine, phenytoin and lidocaine (which is also classed as a class Ib antiarrhythmic).

Question 13

Name three all-or-none physiological phenomena characterised by positive feedback. Hint: many examples are in the endocrine/reproductive systems from A levels.

Answer 13

• •Parturition (giving birth). Menstrual cycle (ovulation). Vomiting. The action potential. Blood clotting cascade.

Question 14

Draw a diagram showing how depolarisation is a positive feedback loop.

Answer 14

Question 15

Name two kinds of synapses.

Answer 15

• Chemical synapses, electrical synapses. Also inhibitory and excitatory.

Question 16

What is the conduction velocity for an alpha motor neuron?

Answer 16

• 100 meters/second

Question 17

What is the conduction velocity for C fibres for pain?

Answer 17

• 1 meter/second

Question 18

What are the structural differences between alpha motor neurons and C fibres responsible for the difference in their conduction velocity? Explain which structural features increase and which decrease conduction velocity.

Answer 18

• Alpha is large diameter and myelinated, both of which increase conduction velocity.
• Myelination increases transmembrane resistance, which leads to more efficient electrotonic signalling inside the axon between nodes of Ranvier.
• Increased diameter leads to increased conduction velocity because intracellular resistance along the length of the axon is lower. This leads to more efficient (hence faster) electrotonic transmission.

Question 19

Why do neurons with a larger cross sectional diameter conduct faster?

Answer 19

• Larger diameter means that along the length of the intracellular fluid of the axon there is less resistance and higher conductance.
• Using the river rapids metaphor, a wider river (higher conductance) leads to more flow (current) for the same drop in height (voltage)

Question 20

Why does myelination lead to increased conduction velocities?

Answer 20

• Myelination increases the transmembrane resistance and decreases the transmembrane capacitance.

Question 21

What are the Nodes of Ranvier and what is their purpose?

Answer 21

• The nodes of Ranvier are thin, unmyelinated strips of membrane along the length of a myelinated axon.
• The nodes are excitable, the axon under myelin is not
  
  • The nodes have clusters of Na+ channels
  • The “bare” cell membrane at the node is specialised for detecting a distant transmembrane electric field (electrotonically) and then firing an action potential in response to it.
• Nodes of Ranvier are essential to increasing conduction velocity by having action potentials “jump” from one node to the next – so-called saltatory conduction.
• Electrotonic transmission is much faster than starting an action potential, but electrotonic transmission is limited by distance because the signal gets smaller as it travels further from its origin

Question 22

Give an example of a local anaesthetic and explain how they work.

Answer 22

• Lidocaine (lignocaine). These block sodium channels, which raises the threshold of action potentials and thus lowers local excitability

Question 23

How are electrical synapses molecularly coupled?

Answer 23

• Via gap junctions

Question 24

Name 5 ways by which chemical and electrical synapses differ. (do not include duplicate or trivial observations)

Answer 24

• Electrical synapses are: faster, bidirectional, 10-fold thinner gap, no amplification, no plasticity (and thus no learning) *E

Question 25

What is the velocity of blood in a capillary?

Answer 25

• 0.5 mm/second

Question 26

What is the velocity of a person walking?

Answer 26

• ~1 meter/sec

Question 27

Give an example of a selective serotonin reuptake inhibitor and explain how they work.

Answer 27

• SSRIs include well-known antidepressants such as fluoxetine (Prozac), paroxetine, citalopram and fluvoxamine.
• SSRIs block the normal reuptake of serotonin from the synaptic cleft, so serotonin builds up in the cleft, leading to a change in serotonin signalling

Question 28

What would happen if the membrane suddenly became 100X more permeable to Cl¯ ions than to any other ion? Why?

Answer 28

• The membrane potential would become clamped to ECl (e.g. -65 mV) because the chloride current would swamp out all other ionic currents (due to its comparatively high permeability).

Question 29

What is the velocity of blood in the aorta?

Answer 29

• ~1 meter/second

Question 30

What would happen if the membrane suddenly became 100X more permeable to Na+ ions than to any other ion? Why?

Answer 30

• The membrane potential would become clamped to ENa (i.e. +55 mV) because the sodium current would swamp out all other ionic currents (due to its comparatively high permeability).

Question 31

How does sodium channel inactivation affect sodium channel activity during the following phases of the AP: rest, depolarisation, repolarisation, after-hyperpolarisation?

Answer 31

• Inactivation interferes with Na channel conduction after the membrane has been depolarised (but with a delay). It affects the AP as follows:
• Rest – no effect, the membrane has not and is not depolarised
• Depolarisation – no effect, the membrane has not and is not depolarised
• Repolarisation – reduces Na+ conduction massively because, the membrane has been depolarised. Allows faster repolarisation (mediated by K+ conductance
• After-hyperpolarisation – initially reduces Na+ conduction massive because the membrane has been depolarised, but over time recovery from inactivation occurs because the membrane is not depolarised.

Question 32

How do neurons encode intensity of a signal?

Answer 32

• Increased frequency, or different neurons for different signal strengths

Question 33

If a neuron was regularly being stimulated but to a subthreshold potential, would it be possible for a subthreshold stimulus onto that neuron via a different synapse to cause an action potential? Why? What is this issue called?

Answer 33

• The phenomenon where two different inputs to a neuron, which are both subthreshold, lead to an action potential is called spatial summation. What happens is that each stimulus partially depolarizes the membrane when creating the EPSP. Each increase in voltage takes that part of the membrane closer to threshold.

Question 34

Define convergent signalling and give an example where it occurs.

Answer 34

• Convergent signalling is when inputs from multiple neurons converge upon a single neuron, so often there are multiple inputs leading to a single “processed” output. Examples are everywhere in the nervous system and include: sensory organs (eg retina and cochlea), the thalamus, the basal ganglia

Question 35

At the resting membrane potential, which force is stronger: the chemical (diffusional) force on K+ ions, or the electrical force on K+ ions? Explain.

Answer 35

• At the RMP the chemical force on K+ is 90 mV outward (as it always is), while the electrical force on K+ is ~80 mV inward, so the chemical force is slightly stronger.

Question 36

What would happen to the resting membrane potential if extracellular Na+ suddenly increased? Why?

Answer 36

• Not much would happen to the resting membrane potential if extracellular Na+ went up a bit, because the RMP is mostly dependent on K+. What would happen is that ENa (driving Na+ into the cell) would become more positive, and the RMP might become slightly less negative.

Question 37

What would happen to the resting membrane potential if extracellular K+ suddenly increased? Why?

Answer 37

• If extracellular K+ suddenly increased, EK driving K outward would be reduced (ie become less negative). Because EK is the major determinant of the RMP, the RMP would become less negative

Question 38

Give two examples where graded potentials occur that have physiological effects.

Answer 38

• Sensory receptor cells (retina, cochlea, taste buds, etc). Synapses.

Question 39

Why don’t graded potentials propagate long distances?

Answer 39

• Graded potentials diminish over distance because voltage approaches zero as it travels along a resistor – and all biological fluids (and membranes) act as resistors. Graded potentials (unlike action potentials) are not re-amplified and restored.

Question 40

Name 5 ways action potentials differ from graded potentials.

Answer 40

• Action potentials are: Fast. All-or-none. Amplified. Can travel long distances. Spiky. Stereotyped voltage changes. Last a consistent duration of time
• Graded potentials are: Electrically localised. Slow to return to the resting potential. Variable in voltage. Variable in duration. Much Flatter. Decreased in voltage as they move. Conduct quickly

Question 41

Why do axons need action potentials (rather than graded potentials) to propagate signals long distances?

Answer 41

• Because action potentials restore and re-amplify signals, so that those electrical signals can travel with fidelity (ie without loss of voltage or information) down long lengths of axon. A small receptor cell (eg rods and cones) can afford to have receptor potentials that are graded potentials because those cells do not send signals long distances inside that cell – they send their signals long distances by transferring the information to another neuron which will use action potentials.

Question 42

Do K+ ions move across the membrane at the equilibrium potential for K+, and why?

Answer 42

• Yes. K+ ions will move back and forth, although the net movement at the equilibrium potential will be nil because the numbers moving in will be the same as the numbers moving out, which happens because the forces on K+ (electrical and chemical) will be equal but opposite.

Question 43

Why is it impossible for an electrical synapse to transmit forward a signal if the post-synaptic cell is much bigger than the pre-synaptic cell?

Answer 43

• Electrical synapses allow for a direct electrical connection between the two cells (using gap junctions). This means that the connection between the two cells includes a resistance and a capacitance. A problem arises if the presynaptic cell is electrically small compared to a larger post-synaptic cell because 1) potentials are reduced as they are communicated along the length of a resistor, and 2) the post-synaptic cell acts as a capacitor, and if the pre-synaptic cell is small, the finite charge it communicates will “be absorbed” by the larger capacitance of the post-synaptic cell, i.e. the potential differences the pre-synaptic cell induces will be smaller in the cell with a larger capacitance than it has. So although it may communicate the electrical signal, the larger capacitance in the post-synaptic cell will make the change smaller.

Question 44

What does the Nernst equation calculate?

Answer 44

• The relationship between the chemical diffusional force caused by an ionic gradient, and its equivalent electrical force. It formally calculates the equilibrium potential, which is the voltage when there is no net current mediated by a particular ion because the chemical and electrical forces balance.

Question 45

What would happen if “delayed rectifier” K+ channels were not “delayed”, i.e. these K+ channels opened immediately upon depolarisation?

Answer 45

• When K+ channels open, Vm moves toward EK, which is how the action potential normally repolarises. The timing of the action potential is such that the delayed rectifier channels open AFTER depolarisation has taken place. It is difficult to say whether the delayed rectifier K+ currents at their peak are larger than the depolarising Na+ currents at their peak (because the Na+ currents always inactivate before the K+ currents can be compared to them). However, if the K+ channels open immediately (ie simultaneously with the Na+ currents of depolarisation), the depolarisation would definitely be slower and smaller, if it occurred at all.

Question 46

Name 5 ways to initiate a subthreshold stimulus in a neuron that might lead to an action potential.

Answer 46

• EPSP from a synapse, an electrical signal from a nearby part of the same neuron (which travels as a graded potential), a signal via an electrical synapse, a receptor cell transducing a stimulus (eg light hitting rhodopsin), a change in extracellular ion concentration (e.g. an increase in extracellular K+)

Question 47

During the after-hyperpolarisation, Vm becomes more negative than the RMP. Why?

Answer 47

• The RMP approaches (but but is slightly more positive than) EK. Compared to the RMP, Vm during the AHP is driven more negative by:
• An increased K+ current due to the delayed rectifier (because there is a time delay for the channels to close after repolarisation)
• A decreased Na+ current (because Na+ channels will still be inactivated from the previous depolarisation due to a time delay)
• An equivalent amount of inward rectifier K+ current outward (ie inward rectifier has almost no delay and is dependent on negative voltage to open, which is true during both AHP and during RMP)

Question 48

The nicotinic acetylcholine receptor is a ligand-gated non-selective cation channel, which means that when it is in the presence of acetylcholine, it will act as an open ion channel that conducts both Na+ and K+. If you assume that when it is open it is equally permeable to Na+ and K+, what would be its equilibrium potential. Explain this in terms of conductances and equilibrium potentials of various ions.

Answer 48

• If you assume that the channel has equal permeability to Na+ and K+ (actually it is not quite equal), then the equilibrium potential for the channel would be the voltage directly between the EK (-90 mV) and ENa (+55 mV). This is because the net voltage across a membrane is the weighted average of the equilibrium potentials, where the weighting is based on the conductances (i.e. if there is more conductances for K+ when the cell is at rest, then the resting membrane potential will be close to EK). In this case, if the conductances for the two ions is equal, the net voltage would be the voltage directly between +55 and -90 is -17.5 mV. You can calculate this via: -90 + ((55 + 90)/2).
• In actual fact, the equilibrium potential for the nAChR is ~ 0 mV, because the permeabilities are not exactly equally balanced.

Question 49

Some diuretics used for hypertension (e.g. non-K-sparing diuretics such as thiazides) cause a net loss of blood K+ via urinary excretion. What would you expect to happen to neural resting membrane potentials, EK, AP thresholds, and excitability in moderate hypokalaemia? It turns out that moderate hypokalaemia leads to muscle weakness and myalgia, and severe hypokalaemia leads to flaccid paralysis. Does this clinical picture fit with what you know about action potentials?

Answer 49

• Hypokalaemia would mean that there is less extracellular K+ (but the same amount of intracellular K+ initially). This would mean that the driving force pushing K+ out of the cell would be greater, and that EK would be more negative. That would make the resting potential more negative, and it would make the threshold more negative. All this would lower excitability. Muscle weakness and flaccid paralysis would be the results of slightly and greatly diminished excitability, respectively.

Question 50

If Nodes of Ranvier speed up conduction velocity via saltatory conduction, would increasing the space between nodes lead to much faster conduction?

Answer 50

• up to a point, increasing the inter-nodal distance will increase conduction velocity, but if the nodes were too far apart, there would be no conduction because the downstream node would not fire an action potential. The further apart two nodes are, the more potential difference (in voltage) will diminish along the length of the axon, making it less likely that the next node will reach threshold based on the conduction of the electric field from the previous node.

Question 51

The conduction of a signal along an axon is accelerated if the axon is wider. Explain this in terms of resistances, capacitances and graded potentials. The conduction is made even faster by myelination. Explain this in terms of resistances, capacitances and graded potentials.

Answer 51

• Resistance determines where currents go (toward the lower resistance). As current and charge (the graded potential) goes along the length of an axon, the current has a choice of going further along the axon, or across the axon membrane. If the current goes across the axon membrane, that reduces the transmembrane potential. If the transmembrane potential is reduced that means the next segment of the membrane is less likely to fire because the ion channels of the AP are triggered by the electric field of the previous bit of axon. Ultimately they will fire, but later, which makes conduction more slow. When the cross-sectional area inside the axon becomes larger, it makes the internal resistance smaller, so more current will travel along the axon as opposed to crossing the membrane. Hence the signal will travel faster.
• •Capacitance is the ability to maintain charge separation (and thus electric fields). Myelin increases capacitance (and vastly increases the resistance across the membrane). As such, myelin sustains the electric field across the membrane and prevents dissipation of charge across the membrane. The graded potentials traveling along the length of the myelinated axon are strong and have enough electric field to trigger Na+ channels to open at a long distance (the next node of Ranvier). As electric fields travel instantly (while it takes time for a new action potential to amplify the signal), in effect myelin allows the AP to jump from one node to the next, which greatly speeds up conduction.

Question 52

If during the relative refractory period Vm is more negative than at rest, which means more driving force for sodium, would it be easier to fire an action potential (ie would excitability be increased during the relative refractory period)?

Answer 52

• No.
• Excitability is determined by how easy it is to depolarise the cell to the threshold potential.
• HOWEVER, the threshold potential is NOT always the same — it can be changed by interfering with the balance of K+ and Na+ currents.
• The threshold condition (ie the threshold potential) is the potential at which the inward current via voltage-gated Na+ channels just exceeds the total outward current (mostly via K+ channels). When voltage-gated Na+ current (which makes the membrane more positive and thus opens more Na+ channels) exceeds outward current, a positive feedback cycle begins, making full depolarisation inevitable.
• •During the absolute refractory period, many Na+ channels are inactivated, reducing Na+ channel current, so the threshold voltage becomes impossibly high because there are not enough Na+ channels capable of conducting to reach the threshold condition.
• During the relative refractory period, most Na+ channels have recovered from inactivation, but there remains high outward K+ current (compared to at rest). This excess outward current makes it harder to reach the threshold condition.
• Thus despite the increased Na+ drive during the relative refractory period, the increased K+ outward current (making threshold voltage higher) is the dominant effect during the relative refractory period.

Question 53

What is the definition of Na+ channel inactivation? What will happen to the excitability if the cells are held in a slightly depolarised state?

Answer 53

• Channel “INactivation” is the process whereby depolarisation of the membrane leads to reduced (or eliminated) channel conductance; keep in mind that “activation” (of voltage gated Na channels) is when depolarisation leads to increased conduction. Na+ channel inactivation means that as the membrane remains slightly depolarised (eg during low level stimulation at synapse), the ability of the Na channel to conduct is compromised, such that even if the membrane is further depolarised (by greater synaptic activity), it is harder to reach the threshold where the positive feedback of action potential depolarisation can begin. a raised threshold means lower excitability.

Question 54

Imagine that there is a drug, and at the dosage you administer that drug, it has side effects. The drug blocks half the K+ current (both delayed and inward rectifiers) but it upregulates the Na/K pump such that its activity is doubled. What would you expect to happen to the resting membrane potential and to the action potential? Draw a very approximate neural action potential under the influence of this drug, and compare this action potential to a normal neural action potential. In your action potential drawings, include axes, axis labels, units and approximate values.

Answer 54

• If the K+ current is half blocked, the resting membrane potential will not be as close to EK – it will be depolarized, possibly by as much as half. By contrast, if the Na/K pump activity is doubled, its electrogenic effects will be double. However, the electrogenic effects only hyperpolarise the membrane by 3 mV, so the resting membrane potential will be an additional 3 mV more negative. However, the effects on K+ channels will have a very strong effect on the RMP. One might imagine that the RMP will move up toward ECl – possibly going as high as -65 mV. In addition, because the delayed rectifiers are half blocked, the repolarisation of the AP will be delayed, and the AP will become wider in duration.