The Myelin Sheath and Action Potentials Case File

The Myelin Sheath and Action Potentials Case File

EUGENE C.TOY, MD, RAHUL JANDIAL, MD, PhD, EVAN YALE SNYDER, MD, PhD, MARTIN T. PAUKERT, MD

CASE 4

A 37-year-old male has had several bouts of neurological deterioration which have each improved with time. His initial complaint was of several bouts of blurry vision which spontaneously resolved. Following these complaints, he developed temporary weakness of his right leg and difficulty with walking. Again, these symptoms resolved in time. He presents to your office in Minneapolis, MN, this time with double vision when he attempts to look to either his left or right side. Following several further tests, you diagnose him presumptively based on the multiple attacks and remissions of weakness and eye problems as having multiple sclerosis (MS), which is a disease of the white matter of the central nervous system.

• Describe the characteristics of white matter of the brain.
• What is the mechanism of the weakness caused by white matter degeneration?
• What are the treatment options available to him?

ANSWERS TO CASE 4: THE MYELIN SHEATH AND ACTION POTENTIALS

Summary: A 37-year-old male with bouts of various waxing and waning neurological deficits is diagnosed with multiple sclerosis.

• White matter characteristics: White matter within the brain consists of myelinated axons that connect various gray matter areas where neuron cell bodies are located to each other by carrying nerve impulses between neurons.
• Mechanism of weakness: MS causes the gradual deterioration of the protective myelin sheaths around axons (demyelination) that facilitate signal conduction. Without myelin, the neurons cease to effectively conduct their electrical signals, resulting in a myriad of clinical symptoms (some presented above). MS is categorized as an autoimmune disease where lymphocytes attack the myelin surrounding axons as if it were a foreign agent.
• Treatment options: Beta interferon can help to reduce the number of exacerbations. High-dose intravenous corticosteroids or intravenous immunoglobulin can be administered to reduce the severity and duration of active attacks. Several other medications have been approved by the Food and Drug Administration to treat symptoms of MS.

CLINICAL CORRELATION

MS is a demyelinating disease affecting only the white matter of the cerebrum, brain stem, and the spinal cord. For an unknown reason, MS is more common in northern latitudes with an incidence of 30–80 per 100,000 in northern United States and Canada compared to 1 per 100,000 near the equator. MS is generally believed to be an autoimmune disease with the myelin sheaths in the CNS coming under attack from the immune system. The plaques start as an inflammatory response with monocyte and lymphocytic perivascular cuffing, followed by the formation of glial scars. Imaging and pathological studies demonstrate white matter plaques of various ages distributed throughout the CNS. The typical course of MS is of exacerbations and remissions over time. The most common symptoms include visual disturbances, spastic paraparesis, and bladder dysfunction. Intranuclear ophthalmoplegia (INO) is a visual disturbance commonly associated with MS that results from a lesion in the midbrain affecting the medial longitudinal fasciculus (MLF). This lesion prevents the oculomotor nuclei and the abducens nuclei from coordinating their movements through the MLF. With lateral gaze, the contralateral medial rectus fails to adduct the eye, while the ipsilateral lateral rectus abducts the eye. The dyscoordinated movements of the eye result in diplopia. MRI scans are the preferred imaging modality for diagnosis of this disease. Approximately 80% of individuals with a clinical diagnosis of MS will exhibit white matter abnormalities on MRI scans. Analysis of the CSF from a lumbar puncture generally demonstrates normal opening pressures and increased CSF protein levels. CSF-IgG is increased relative to other CSF proteins in approximately 90% of patients with definite MS. Gel electrophoresis of the CSF reveals oligoclonal bands. Diagnosis relies on a combination of patient history and physical examination supported by imaging and CSF study results. While there is no cure for MS, there are several treatment strategies available to slow the progression of the disease, reduce the frequency of attacks, and to shorten the duration of attacks.

APPROACH TO THE MYELIN SHEATH AND ACTION POTENTIALS

Objectives

1. Describe what constitutes the myelin sheath and understand its role.
2. Describe how the action potential is propagated through the axon.
3. Describe the variables that affect the conduction velocity of the axon.

Definitions

Nodes of Ranvier: The region of the axon between consecutive myelin sheaths with high concentrations of ion channels which allow for current flow.

Saltatory conduction: A type of rapid conduction of an electrical potential at the nodes of Ranvier skipping myelinated segments along the axon. Because the cytoplasm of the axon is electrically conductive, and because the myelin inhibits charge leakage through the membrane, depolarization at one node of Ranvier is sufficient to elevate the voltage at a neighboring node to the threshold for action potential initiation allowing action potentials to hop along an axon instead of propagating in waves.

Threshold: An irreversible point at which the initial depolarization of the membrane results in the rapid opening of all of the voltage-gated ion channels, usually action threshold potentials are around −45 mV.

Axon hillock: The region of the neuron between the cell body and the axon which generates action potentials.

Refractory periods: The period of time in which it is either impossible or difficult for additional stimuli to generate another action potential.

DISCUSSION

Myelin sheaths are produced by the oligodendrocytes in the central nervous system and by Schwann cells in the peripheral nervous system. It is important to note, however, that not all axons are encased in myelin sheaths. Myelin consists of lipids and membrane proteins which are wrapped in circumferential layers around segments of axons. The intervals between adjacent myelin sheaths are called the nodes of Ranvier and are important for conduction of the action potential.

During the development of the peripheral nervous system, Schwann cells become closely associated with developing bundles of axons within the nerve. A single Schwann cell provides a single segment of the myelin sheath for the developing axon. As axons grow and elongate, the Schwann cells divide by mitosis to ensure complete coverage of the selected axon. This is in contrast to the central nervous system where oligodendrocytes extend processes to multiple axons to provide myelin sheaths. One oligodendrocyte can provide a segment of myelin for up to 60 different axons. Myelin sheaths are laminated when examined by electron microscopy caused by the sequential wrapping of the myelin around the axon. During this wrapping process, the cytoplasm of the Schwann cells and oligodendrocytes are squeezed out of the developing myelin sheath. In the end, the layers of the cell membrane are opposed and are secured in place by proteins, such as myelin basic protein, proteolipid protein, and protein zero, that are embedded in the lipid membrane.

At the nodes of Ranvier, the myelin sheaths meet, but do not join. In this region, the axon is exposed to the extracellular environment. The voltage gated ion channels necessary for the saltatory conduction of the action potential are concentrated in this region of the axon.

A typical action potential lasts for less than 1 ms, and is elicited in an allor- nothing fashion. Neurons code the intensity of a stimulus by the frequency, not the amplitude of action potentials. The action potential is crucial for the passage of information via electrical impulses over long distances and is generated by voltage-gated ion channels. These channels alter their selective permeability to a specific ion based upon changes in the transmembrane potential. Specific voltage-gated channels include Na+, K+, and Ca2+ channels. The action potential is a regenerative signal that does not lose amplitude as it travels down the axon and rely on voltage-gated Na+ and K+ channels.

The tertiary structure of the voltage-gated ion channel is determined by the transmembrane potential in the local environment. With changes to the transmembrane potential, the channel either opens or closes to modulate the flow of ions. These channels are typically open for a very short period of time, 10 μs or less, and function as an “all-or-nothing” type response. At the resting membrane potential of neurons, the voltage-gated Na+ and K+ channels are generally in their closed configuration.

The action potential is generated at the axon hillock, the region between the soma of the neuron and the axon, which contains a higher number of voltage-gated Na+ channels than anywhere else in the neuron. As the neuron receives signals from the dendrites and soma, they converge at the axon hillock. As the stimulus is received, some of the voltage-gated Na+ channels open resulting in the influx of positive Na+ ions into the cell and a small depolarization of the axon hillock. If the stimulus is strong enough, it will cause more and more of the voltage-gated Na+ channels to open through positive feedback by the Na+ ions until a point is reached where the depolarization becomes irreversible. This point is called the threshold (Figure 4-1). The Na+ channels remain open for a brief period of time before it is inactivated by a conformational change that results in channel closing.

The depolarization also affects the voltage-gated K+ channels. However, these channels open more slowly and for a longer period of time in response to the initial depolarization and allow K+ ions to flow out of the cell. The peak flow of K+ ions occurs as the sodium current is decreasing. This results in repolarization. In the later stages of the action potential, the K+ efflux is unopposed and drives the transmembrane potential past the resting potential and closer to the equilibrium potential for K+ ions. As the voltage-gated K+ channels close, the resting channels allow for the reestablishment of the resting membrane potential.

Figure 4-1. Components of an action potential.

Shortly after threshold is reached, there is a period of time where additional stimuli will not result in any action potential. This is termed the absolute refractory period and is owing to the already maximal opening of the Na+ channels. The Na+ channels begin to close even in the presence of continued presence of the depolarization; the channels become inactivated and it takes time for them to recover from the inactivation before they are able to open again. Na+ is critical for the action potential: if the extracellular concentration of Na+ decreased the amplitude of the action potential would decrease. Following the peak of the action potential, additional supernormal stimuli may result in the generation of another action potential. This period is the relative refractory period. As the K+ channels close, the membrane slowly approaches its resting membrane potential. Typically, repolarization of the cell by closing K+ channels results in an overshoot of resting membrane potential, creating a refractory period where the membrane potential equalizes to resting state. During this period, the nerve can be restimulated to fire an action potential by a supernormal stimulus. A larger than normal depolarizing stimulus is required to overcome the overshoot during repolarization by the voltage-gated K+ channels.

For a neuron to signal other cells over distances, the action potential must be propagated down the length of the axon. The initial depolarization and resulting action potential occurs in only a small segment of the axon creating a local current. This depolarizing current travels distally down the axon and results in the next segment under threshold reaching threshold. This segment then generates another action potential, ensuring that the amplitude of the signal is not attenuated as it travels. The signal can only travel in a unidirectional fashion because of the refractory period of the channels.

The conduction velocity of the fastest axons in the human body transmits action potentials at a rate of 120 m/sec through large, myelinated axons. Smaller, unmyelinated axons conduct action potentials at approximately 0.5 m/sec. In invertebrates, such as the well-studied squid giant axon, conduction velocities are increased by increasing the diameter of the axon up to 1 mm. This strategy decreases the resistance through the axon. Mammals, which tend to have much smaller axons, employ myelin sheaths to increase the membrane resistance of the axon resulting in faster conduction velocities.

Because of the myelin sheaths, voltage-gated channels are clustered at the nodes of Ranvier and are the only points along a myelinated axon where currents can be generated. Furthermore, the myelin sheaths prevent any significant loss in amplitude of the action potential at the internodal segments, the region of the axon covered by myelin. This allows the signal to jump quickly from one node of Ranvier to another while skipping the internodal segments, a process termed saltatory conduction (Figure 4-2). In unmyelinated axons, the current spreads more slowly because of the decreased membrane resistance and lack of saltatory conduction.

Figure 4-2. Schematic diagram of action potential traveling down an axon via saltatory conduction.

Although the two channel system examined in the Nobel Prize winning work by Alan Hodgkin and Andrew Huxley in the squid giant axon is found in almost every type of neuron, there are several other types of voltage-gated ion channels. This diversity allows for a much more complex information processing system.

COMPREHENSION QUESTIONS

[4.1] In preparation to excise a mole from a patient’s back, the physician injects lidocaine into the surrounding skin to anesthetize the area. Lidocaine acts by binding to and preventing opening of the voltage-gated sodium channels, thus preventing transmission of impulses down the axon. What segment of the action potential is blocked by the action of this drug?

A. Rapid depolarization

B. Delayed rectifier current

C. Repolarization

D. Resting potential

[4.2] During a neuroscience laboratory exercise, you are experimenting with the response of a neuron to various electrical stimuli. You notice that there is a short time period following the action potential when no matter how much you depolarize the membrane, you cannot stimulate an action potential. What is the molecular mechanism responsible for this phenomenon?

A. Undershoot hyperpolarization

B. Inactivation of sodium channels

C. Closing of voltage-sensitive sodium channels

D. Opening of voltage-sensitive potassium channels

[4.3] Immediately following the time frame in the previous question is a time period when an action potential can be generated, but only when a larger than normal stimulus is applied. What is the molecular mechanism responsible for this phenomenon?

A. Opening of voltage-gated sodium channels

B. Opening of voltage-gated potassium channels

C. Slow closing of voltage-gated potassium channels

D. Slow closing of voltage-gated sodium channels

Answers

[4.1] A. Lidocaine binds to inactivated sodium channels, preventing the rapid depolarization needed for the initiation of the action potential. The opening of the voltage-gated sodium channels is responsible for the rapid upstroke of the action potential. Slower acting voltagesensitive potassium channels are responsible for the delayed rectifier current, which, in combination with the closing of voltage-sensitive sodium channels, are responsible for repolarizing the axon.

[4.2] B. The time period referred to in the question is caused by inactivation of voltage-sensitive sodium channels and is known as the absolute refractory period. During this time period, which immediately follows repolarization, the voltage-sensitive sodium channels assume a configuration in which they will not open, regardless of membrane potential. Undershoot hyperpolarization, the time following the action potential when the membrane is more negative than the resting potential, is responsible for the relative refractory period. During this time, an action potential can be elicited, but it requires a larger stimulus as the membrane must be depolarized further to reach threshold. Closing of voltage-sensitive sodium channels and opening of voltage-sensitive potassium channels both contribute to neuronal repolarization.

[4.3] C. The question refers to the time period known as the relative refractory period, which is caused by the slow closing of voltage-gated potassium channels. During this time period an action potential can be triggered, but because the membrane is hyperpolarized, a larger stimulus is required to reach threshold. The reason that the membrane becomes hyperpolarized following an action potential is because of the slowness of response of the voltage-gated potassium channels. This slowness of response results in the potassium channels staying open longer than necessary to repolarize the membrane, resulting in a transient hyperpolarization or undershoot. As the potassium channels close, the hyperpolarization resolves and the membrane returns to its resting potential.

NEUROSCIENCE PEARLS ❖ The nodes of Ranvier, the intervals between adjacent myelin sheaths, are important for characteristic saltatory conduction of the action potential down an axon. ❖ Whereas Schwann cells only myelinate one axon, oligodendrocytes extend processes to myelinate multiple axons. ❖ Action potentials are elicited in an all-or-nothing fashion. Intensity of the stimulus is encoded in frequency, not amplitude of the action potential. ❖ Signals from the neuron’s dendrites and soma converge at the axon hillock, resulting in a small depolarization of the axon hillock. A sufficiently strong stimulus will cause more voltage-gated Na+ channels to open through positive feedback by the Na+ ions until depolarization becomes irreversible (threshold). ❖ The absolute refractory period occurs when the Na+ channels, after having been maximally open, assume an inactivated configuration in which they will no longer open, regardless of membrane potential. ❖ The relative refractory period occurs after the absolute refractory period and is owing to slow closing of K+ channels.

REFERENCES

Bear MF, Connors B, Paradiso M, eds. Neuroscience: Exploring the Brain. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006. 

Purves D, Augustine GJ, Fitzpatrick D, et al., eds. Neuroscience. 3rd ed. Sunderland, MA: Sinauer Associates, Inc; 2004. 

Zigmond MJ, Squire LR, Bloom FE, Landis SC, Roberts JL, eds. Fundamental Neuroscience. 2nd ed. San Diego, CA: Academic Press; 1999.

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