What is the mechanism by which myelination reduces the capacitance of the axon membrane?

There are two mechanisms that have been proposed to me.

1) Layering of Schwann cell membrane with conducting fluid between the layers is analogous to several capacitors in series. Since capacitance in series add by the reciprocal rule (as resistors do in parallel), this reduces the total capacitance.

2) The myelin increases the distance between the 'plates' of the capacitor. For parallel plate capacitors $ C = epsilon A/d$ where d = distance between the plates. Thus increasing the distance reduces the capacitance.

Which of these explanations best applies to myelin, or is it in fact a mixture of both?

Circuit analogies don't 100% apply to myelin because membranes have complex electrical properties, but both of those explanations work and they are in fact essentially interchangeable: Take a membrane with distance d across the membrane and capacitance c. Then we add some myelin to get a new capacitance C at a new distance D.

If you 4X the distance between plates (D = d * 4), C=c/4 (from the formula you posted as (2) ); if you add 3 extra plates (so now you have a total of 4 plates), C=1/(1/c + 1/c + 1/c + 1/c)=c/4.

Importantly, myelin also increases the membrane resistance, and because myelin is typically very thick compared to a normal membrane (~10nm for one layer vs. 500-2500nm for myelin), you can almost consider myelination to increase resistance to infinity (compared to the axial resistance of cytoplasm) and the capacitance to zero.

See this page for some more info.

Note that the reason these explanations are interchangeable is that there is effectively no distance between the added plates in series and no difference in capacitance for each individual capacitor/piece of membrane (for example, see this page).

Formation and Maintenance of Myelin

Wendy B. Macklin , . Wendy B. Macklin , in Basic Neurochemistry (Eighth Edition) , 2012

Maintenance of myelin once it is formed is a poorly understood process 577

Myelin components exhibit great heterogeneity of metabolic turnover 577

There are signal transduction systems in myelin sheaths 577

The dynamic nature of myelin sheaths likely contributes to the functional state of axons 578

Peripheral neuropathies result from loss of myelin in the peripheral nervous system 578

A number of environmental toxins impact myelination during development or myelin maintenance in the adult 578

Leukodystrophies define a number of genetic disorders that impact CNS myelination (dysmyelination) or myelin maintenance once it is formed (demyelination) 578


JEFFERY D. KOCSIS , . CHRISTINE RADTKE , in CNS Regeneration (Second Edition) , 2008


Demyelination in the central nervous system (CNS) occurs in a variety of pathophysiological conditions. Perhaps the most notable is demyelination associated with multiple sclerosis (MS). MS is an inflammatory disease characterized by white matter plaques of demyelination in the brain and the spinal cord ( Charcot, 1868 Lumsden, 1970 ). In addition to demyelination, MS plaques are often associated with axonopathy ( Trapp et al., 1999 ). Impulse conduction is either blocked or slowed in these lesion sites resulting in various neurological symptoms depending on the plaque site. Demyelination can also occur in traumatic spinal cord injury (SCI) and following cerebral infarction. In contusive SCI, the spinal cord often presents with a central necrotic core, but areas of demyelinated axons are present outside of this region. Interestingly, apoptotic oligodendrocytes have been observed in experimentally induced SCI models at considerable distances of the injury sites ( Crowe et al., 1997 ). Thus, interventional approaches to encourage CNS remyelination have relevance to many immunologic and traumatic CNS disorders. Experimental cellular transplantation has proven successful in a number of demyelination and injury models to remyelinate and improve functional outcome. Here we discuss the remyelination and neuroprotective potential of several myelin-forming cell types and their behavior in different demyelination and injury models. Better understanding of experimental cell-based strategies for remyelination and neuroprotection offer exciting opportunities to develop strategies for clinical studies.


Diseases that result in injury to the oligodendroglial cells include demyelinating diseases such as multiple sclerosis and various leukodystrophies. Trauma to the body, e.g. spinal cord injury, can also cause demyelination.

The immature oligodendrocytes, which increase in number during mid-gestation, are more vulnerable to hypoxic injury and are involved in periventricular leukomalacia. This largely congenital condition of damage to the newly forming brain can therefore lead to cerebral palsy.

In cerebral palsy, spinal cord injury, stroke and possibly multiple sclerosis, oligodendrocytes are thought to be damaged by excessive release of the neurotransmitter glutamate. Damage has also been shown to be mediated by N-methyl-D-aspartate receptors.

Oligodendroglia are also susceptible to infection by the JC virus, which causes progressive multifocal leukoencephalopathy (PML), a condition that specifically affects white matter, typically in immunocompromised patients. Tumors of oligodendroglia are called oligodendrogliomas.

The chemotherapy agent Fluorouracil (5-FU) causes damage to the oligodendrocytes in mice, leading to both acute central nervous system (CNS) damage and progressively worsening delayed degeneration of the CNS.

Function Of Schwann Cells

[caption align=&ldquoalignright&rdquo width=&ldquo310&rdquo] Portrait of Theodor Schwann. Wellcome Images[/caption]

The vertebrate nervous system relies on the myelin sheath for insulation and as a method of decreasing membrane capacitance in the axon. The action potential jumps from node to node, in a process called saltatory conduction, which can increase conduction velocity up to ten times, without an increase in axonal diameter.

In this sense, neurolemmocytes are the peripheral nervous system&rsquos analogues of the central nervous system&rsquos oligodendrocytes.

However, unlike oligodendrocytes, each myelinating Schwann cell provides insulation to only one axon. This arrangement permits saltatory conduction of action potentials with repropagation at the nodes of Ranvier. In this way, myelination greatly increases speed of conduction and saves energy.

Non-myelinating Schwann cells are involved in maintenance of axons and are crucial for neuronal survival. Some group around smaller axons and form Remak bundles.

[caption align=&ldquoalignright&rdquo width=&ldquo321&rdquo] Schwann cell myelinating axons.
Credit: Dr David Furness, Wellcome Images[/caption]

Myelinating Schwann cells begin to form the myelin sheath in mammals during fetal development and work by spiraling around the axon, sometimes with as many as 100 revolutions. A well-developed Schwann cell is shaped like a rolled-up sheet of paper, with layers of myelin in between each coil.

The inner layers of the wrapping, which are predominantly membrane material, form the myelin sheath while the outermost layer of nucleated cytoplasm forms the neurilemma. Only a small volume of residual cytoplasm allows communication between the inner and outer layers. This is seen histologically as the Schmidt-Lantermann incisure.


Neve impulses are generated by ion courrent (carried chiefly sodium ions) flowing into an axon at an "active zone" where the voltage-gated sodium channels present are open. In unmyleinated axons (see figure below) most of the current spreads to regions close to the active zone because it exits the axon the high capacitance and leak-conductance of that membrane. In myelinated fibers, on the other hand (see scond figure below), active zones are restricted to the axonal membrane exposed at the nodes. The multiple layers of dielectric presented by the myelin sheath proportionately reduce the trans-fiber capacitance compared to a non-myelinated fiber. This in turn greatly reduces the radial leakage of transient currents flowing through the sheath during nerve impulses (current flowing through a capacitor is proportional to the time derivative of voltage-change across it) in regions between nodes (the "internodes"). Although sodium channels are concentrated at the nodes at densities well above those of typical unmyelinated fibers, the mean density averaged over the length of the fiber is much less, resulting in a smaller ionic imbalance that must be restored at the expense of metabolic energy (ionic pumps) after an impulse passes. The smaller internodal current loss leaves more current available to raise distant nodes to threshold, which will thus happen more quickly, speeding impulse propagation. Further, the reduced size of exposed nodal membrane, reduces the area of membrane into which this current must flow and increases the rate of change of voltage at the node (technically, the time-constant for charging nodal capacitance is reduced), allowing threshold to be reached faster, further speeding the impulses.

Conduction speed also depends on axial resistance through the interior of the fiber. The larger the diameter of this interior space, the lower the resistance, a principle that holds for unmyelinated as well as myelinated fibers. Changing just the diameter of this inner space (typically mostly filled by the axon) gives a conduction speed that varies as the square root of the inside diameter (1/2 power). This explains the frequent observation of "giant" axons in invertebrates, especially prevalent in circuits involved in rapid escape reactions (e.g. Nicol 1947). The thickness of the myelin sheath, however, varies with the interior diameter, typically maintaining a fairly constant ratio to it ( ca 0.7). The result is that internode capacitance per unit area of axon decreases with fiber diameter, adding to the effects from decreased axial resistance and giving the conduction speed a first power dependency on inner (or outer) diameter over a substantial range.

What is myelin and who else has it?

The essential structural features that produce these properties are the restriction of leakage current to cross multiple membrane lamellae in the internode and the reduction of surface area of nodal membrane. If we take these as the defining characteristics of "myelin" then myelin occurs in several taxa of phylogenetically distant invertebrates: among crustaceans of the subclasses malacostraca (including decapod shrimp) and copepoda, and among annelids of the groups polychaeta and oligochaeta. There are several variants in myelin structure seen in invertebrates which still achieve the same functional results.

Vertebrate myelin is spirally wrapped. That is, a continuous double lamella laid down by a Schwann cell or oligodendrocyte winds around the fiber starting against the axon and spiraling outward. Compact myelin is the form most typical of mature vertebrate myelin, with both cytoplasmic and extracellular spaces eliminated. In EM cross section, this gives rise to a regularly banded alternation of thick and thin lines referred to as the "major dense line" (apposed ecytoplasmic membrane leaflets) and the "intraperiod line" (apposed extracellular leaflets). Vertebrate myelin has regions (Schmidt-Lantermann incisures) that retain cytoplasm over short segments and these form continuous spiral intracytoplasmic pathways from just outside of the axon to the outer layer of glial membrane. Spiral wrapping has the disadvantage of requiring specializations to prevent radial current leak following along the spiral path between lamellae.

Reports of myelin in invertebrates are scattered among several phylogenetically diverse groups as shown on the phyletic tree below. Not all of these reports have been confirmed in the electron microscope yet (asterisks in the figure below) and recent EM evidence has failed to confirm its presence in one of the polychaete groups indicated in the figure below (bamboo worms) - see Hartline and Kong (2008).

Myelin of oligochaetes (especially the earthworm) is the best studied of invertebrate myelin at the electron microscope level. It is spirally wrapped, at least in places, as in the vertebrate case (Roots et al. 1991 see figure below). It consists of 20 to 200 layers, often, but not always, compact. The non-compact regions typically have thin layers of cytoplasm sanndwiched between glial cell membranes. Being intracellular and narrow, however, their capability for compromising sheath insulation appears limited. While conduction speed of earthworm myelinated fibers is high compared to that for non-myelinated fibers of the same diameter, the advantage is only a few fold (Gunther, 1976).

All crustacean myelin so far described has proven to be concentrically arranged: lamellae of a given layer encircle the central axon, abutting against corresponding margins of the same layer at the margins. Concentric wraps are electrically more efficient, requiring only that tight seals be made at the margins of the myelinating cells, the "seams," to prevent short circuiting of the insulation. Thus myelin in the decapod shrimp is sometimes compact and sometimes only semicompact, that is, it excludes only the extracellular gap while retaining cytoplasm or vice versa . What is important for its electrical integrity is that the space between layers are sealed from each either by a continuous membranous barrier or by tightly joined appositions at the seams. Two somewhat different forms have been described for different shrimp taxa. In the more "advanced" Caridean shrimp (including the prawns), each myelin layer includes a thin sheet of sandwiched cytoplasm and extends fully around the axon, meeting itself on the opposite side in a seam. The seams of successive layers alternate sides going from inner to outer sheath, producing long electrical paths between seams of adjacent layers (Heuser and Doggenweiler 1966). In contrast, in the more primitive Dendrobranchiata (to which the commercial penaeid shrimp belong), each myelin layer only extends half way around the interior core, with the margins of each half-layer meeting those of a sister layer at the same level coming from the other side (Huang et al 1963). Penaeid fibers are unusual in that the axon occupies only a part of the interior space. The rest is occupied by a glial cell and is termed the "submyelinic space" (Hama 1966). Current entering the axon through voltage-gated channels flows readily out of it again as in non-myelinated nerve, but is trapped and confined in the submyelinic space, as if it were a giant axon filling the space (see figure below). Penaeid axons of 120 microns diameter conduct impulses at the fastest speeds known: over 200 m/s ( cf 100 m/s for the fastest myelinated vertebrate axon)(Kusano 1966).

Of the nodes examined in invertebrates closely enough so far, only the Caridean shrimp ( Palaemonetes ) have circumferential nodes like the vertebrates (Heuser & Doggenweiler, 1966). Earthworms, Penaeids and copepods appear only to have "fenestrated" or "focal" nodes in which only a small piece of the axon is exposed through a gap in the surrounding sheath (Gunther 1976 Hsu and Terakawa 1996 Weatherby et al 2000 see figure below). More than this is not necessary for saltatory conduction to occur, since only a small amount of membrane is needed to accommodate the sodium channels necessary for regeneration of the nerve impulse.

What are the molecular building blocks for myelin and where did they come from?

A plethora of special molecules have been identified in vertebrate myelin, often found exclusively in the structure. Are there shared homologues in different taxa that suggest a common ancestry for some and maybe all cases of myelin evolution? Light and mystery is shed on the origin of vertebrate myelin by the finding that the genome of a protochordate, Ciona (tunicate) contains homologues for several of the myelin tetra-span proteins (membrane proteins with 4 membrane-traversing regions). Thus in vertebrates, some of the molecular antecedents of myelin seem to have been identified. Anomalously, however, homologues of another highly-important class of proteins, the so-called "non-tetraspan" proteins, appear to be completely absent (Gould et al 2005). Among these are those believed responsible for the tight binding of adjacent membrane lamellae in compact myelin. Homologues for these, especially one forming one of the major protein components of peripheral vertebrate myelin, myelin basic protein (MBP), have failed to turn up in any non-vertebrate groups so far examined. Intriguingly, genes homologous to MBP are found in the adaptive immune system (AIS), another gnathostome invention (see e.g. Klein and and Nikolaidis, 2005).

So invertebrates have myelin after all?

As with many valuable evolutionary innovations, complicated though they may be and difficult to assemble with all parts functioning correctly, selective pressures have repeatedly "reinvented the wheel" of myelin in several different groups. Knowing that it can indeed be done, we may wonder why this has not occurred in other highly successful groups such as molluscs and insects. However that may be, because invertebrates (especially copepods) are so numerous, it remains a fact that there are more myelinated INVERTEBRATES on this planet than myelinated VERTEBRATES!

Does invertebrate myelin work differently from vertebrate myelin?

As described above, the myelin insulation forces the current generated by a nerve impulse to spread farther and faster down the center of the axon to the next node, where a new impulse is set up. This is true regardless of which species is being considered. However, the problems of making the insulation electrically impervious to current leak that would compromise sheath efectiveness does differ somewhat from species to species. Species with spirally-wrapped myelin such as vertebrates and annelids must prevent curent escape along a spiral path between glial cell margins, as shown in the figure below on the left. This path can be closed by compacting these faces. The problem for concentric myelin is similar, but it can be solved by either compacting adjacent membrane faces or by sealing the connecting paths between layers where glial margins meet (2nd figure from the left). At nodes, all glially-derived myelin appears to need special junctions termed "septate junctions" betwen the margins of the glial sheets and the axon, as shown in the third figire below. Finally, in copepod myelin, the compacting of the myelin around the node itself appears to be sufficient to prevent curent leak (figure on the right).

What is the mechanism by which myelination reduces the capacitance of the axon membrane? - Biology

Schwann cells embryologically derive from the neural crest. They myelinate peripheral nerves and serve as the primary glial cells of the peripheral nervous system (PNS), insulating and providing nutrients to axons. Myelination increases conduction velocity along the axon, allowing for the saltatory conduction of impulses.[1] Nonmyelinating Schwann cells do not wrap axons to improve conduction, but still, provide trophic support and cushioning to the unmyelinated axons.[2]


Each Schwann cell makes up a single myelin sheath on a peripheral axon, with each ensuing myelin sheath made by a different Schwann cell, such that numerous Schwann cells are needed to myelinate the length of an axon. This arrangement is in contrast to oligodendrocytes, the myelinating cell of the central nervous system (CNS), which form myelin sheaths for multiple surrounding axons. Schwann cells are surrounded by a basal lamina, while oligodendrocytes are not. Between adjacent myelin sheaths, there are gaps of approximately 1 micrometer, called nodes of Ranvier. There is a concentration of voltage-gated sodium channels at the node, which is the site of saltatory conduction.[1] Schmidt-Lanterman incisures are cytoplasmic outpouchings that interrupt compact myelin in heavily myelinated neurons. They contain a high density of gap junctions and other cell junctions, serving a role in communication and maintenance of the Schwann cell.[3]


Schwann cells serve as the myelinating cell of the PNS and support cells of peripheral neurons. A Schwann cell forms a myelin sheath by wrapping its plasma membrane concentrically around the inner axon. While the nucleus remains fixed, the inner turn of the glial cell membrane spirals around the axon to add membrane layers, or lamellae, to the myelin sheath. The plasma membrane of Schwann cells has an extremely high lipid content, and cholesterol is particularly important for assembling the myelin sheath. The compact myelin sheath insulates the axon segment, significantly reducing membrane capacitance and increasing conduction velocity.[1] Neuregulin-type III expression on axons is essential for survival and maturation of Schwann cell precursors, and the degree of myelination depends on the amount of neuregulin on the surface of the axon.[4][5] Schwann cells also provide energy metabolites to axons, shuttling them through monocarboxylate transports available along the surface of the axon and inner membrane of the Schwann cell.[1]

Schwann cells are critical in response to PNS axon damage and axon regeneration. Wallerian degeneration will occur distal to the injury site. The distal axon segment dies and Schwann cells, followed by macrophages, clear the dead cell contents, and promote axon regeneration. Schwann cells undergo several phenotypic changes at this time: they activate myelin breakdown, up-regulate the expression of cytokines (including TNF-a) to recruit macrophages to the injury site, up-regulate neurotrophic factors to stimulate axon regeneration and neuron survival, and organize a regeneration pathway along their basal lamina tube to guide axon growth. Axonotmesis and neurotmesis are the main types of PNS nerve injury. In axonotmesis, such as in a crush injury, the axon suffers disruption, but the basal lamina tube of the Schwann cells remain. The lumen of the tube provides guidance cues to the regenerating axon sprout as it grows, promoting highly effective axon regeneration and restoration of function in 3 to 4 weeks. In neurotmesis, such as in a cut injury, the axon, Schwann cell basal lamina, and surrounding connective tissue sheath are disrupted. The regenerating axon and its associated Schwann cells still grow from the proximal to the distal nerve stump. Because of targeting errors in the absence of the basal lamina tube, correct reinnervation and recovery of function are poor in neurotmesis.[5]

Tissue Preparation

Aldehyde is the preferred routine fixative for nervous tissue. Electron microscopy requires an aldehyde fixative with high purity.[6] After fixation, the sample gets embedded in either paraffin or epoxy. Paraffin allows for the study of the entire cross-sectional area of a nerve and is the preferred medium for light microscopy and larger nerve sections. Epoxy is preferable for smaller nerve branches and visualization with electron microscopy.[7] Recent utilization of cryofixation, high pressure freezing and freeze substitution, is a beneficial supplement to aldehyde fixation in electron microscopy and may improve the preservation of structure detail and contrast.[8]

Histochemistry and Cytochemistry

Immunohistochemical stains are valuable tools to differentiate Schwann cells from other cell types. S-100 is a protein unique to neural crest-derived cells, so anti-S-100 antibodies can be used to stain for healthy Schwann cells or nervous tissue neoplasms, such as schwannomas.[9] Myelin basic protein (MBP) neutralizes phospholipid charges on the inner surface of the membrane and is present in Schwann cells but not satellite cells, the other major PNS glial cell. Anti-MBP can be used to differentiate Schwann cells or oligodendrocytes from other glial cells.[10] P0, a peripheral nerve myelin protein, is a transmembrane adhesion protein that promotes the extracellular lamellar apposition that forms the intraperiod lines.[1] Anti-P0 can be used to identify granular cell tumors, which derive from Schwann cells.[11]

Microscopy Light

Under light microscopy, Schwann cell nuclei and myelin sheath are visible, as well as their basal laminae and associated axons.[12] Both light and electron microscopy demonstrate myelin sheaths of various thicknesses according to neuregulin expression by the axon. More heavily myelinated axons may have more than 40 lamellae, as visualized by alternating intraperiod and dense lines. Intraperiod lines demonstrate the apposition of extracellular surfaces of compact lamellae of the Schwann cell plasma membrane. Dense lines demonstrate the close apposition of the cytoplasmic surfaces of the membrane in compact myelin.[1]

Microscopy Electron

Under transmission electron microscopy, the lamellar structure and Schwann cell cytoplasmic content can be visualized clearly, including mitochondria, microtubules, and microfilaments. Osmium tetroxide is used to stain the myelin, allowing the dark (osmiophilic) myelin of myelinating Schwann cells to be clearly distinguished from the lighter membranes of the non-myelinating Schwann cells. Myelinating Schwann cells can be seen surrounding a single axon with a myelin sheath, though it may also have unmyelinated axons associated with its outer cytoplasm. Bundles of unmyelinated axons are visible, settled into the cytoplasm of a non-myelinating Schwann cell. Endoneurium, the loose connective tissue sheaths that surround individual nerve fibers, can also be visualized.[12]


The major diseases involving Schwann cells are demyelinating or neoplastic processes. Disorders that cause damage to the myelin sheath in the PNS, affecting the function of Schwann cells and axons, are called peripheral demyelinating diseases. Various insults, such as genetic mutations, infections, trauma, and autoimmune processes can trigger this demyelination and eventual neurodegeneration. Guillain-Barre Syndrome is a rare autoimmune peripheral demyelinating disease characterized by acute ascending flaccid paralysis, which can be life-threatening if the disease affects the muscles of respiration. It is often associated with a preceding infection of the gastrointestinal or respiratory tract, particularly C. jejuni and associated anti-GM1 and anti-GD1a antibodies. The association with infection and accumulation of anti-ganglioside antibodies suggests that ganglioside-like antigens found on C. jejuni lead to the production of antibodies that are cross-reactive with myelinating cells of the PNS. Guillain-Barre can also be caused by other pathogens, trauma, surgery, monoclonal antibody treatment, and rarely by vaccination. The patients usually present with proximal muscle weakness of lower extremity. The most common variant of Guillain-Barre is acute inflammatory demyelinating polyradiculopathy (AIDP), which presents histologically with segmental demyelination with lymphocytic and monocytic infiltration.[13][14]

Charcot-Marie-Tooth disease (CMT) is a rare hereditary peripheral demyelinating disorder, most commonly with autosomal dominant inheritance. Several subtypes affect different proteins and can affect both sensory and motor nerves, but all disrupt Schwann cell structure and function. PMP22 is the most commonly affected protein and causes CMT1A, leading to growth arrest in Schwann cells and abnormal Schwann cell number between nodes of Ranvier. CMT1 is characterized by segmental demyelination and remyelination, causing onion skin appearance on biopsy, and greatly reduced conduction velocity of nerves.[13][15] 

Diabetes mellitus is associated with hyperglycemia, hyperlipidemia, hypertension, and impaired insulin signaling, which can damage microvasculature, leading to the common complication of diabetic peripheral neuropathy. Diabetic neuropathy is due to damage to Schwann cells and axons in both sensory and motor nerves. Schwann cells appear to be more susceptible to direct damage caused by hyperglycemia. In contrast, neurons are highly metabolically active, and function better in a hyperglycemic environment but are at greater risk of degeneration caused by hypoxia and loss of trophic support from Schwann cells. Hyperglycemia causes Schwann cell dysfunction, production of reactive oxygen species, initiation of the inflammatory cascade, disruptions in axon conduction, and impaired regeneration after nerve damage.[2]

Schwannomas, neurofibromas, and malignant peripheral nerve sheath tumors (MPNSTs) are all neoplastic conditions that arise from Schwann cells. Schwannomas are typically solitary encapsulated lesions made exclusively of neoplastic Schwann cells. Schwannomas do not invade the associated nerve but may produce symptoms caused by mass effect. Neurofibromas and MPNSTs are made of multiple cell types, including Schwann cells, and commonly infiltrate the associated nerve. Neurofibromas commonly arise in patients with neurofibromatosis 1 (NF1), an autosomal dominant disorder caused by a mutation in the NF1 tumor suppressor gene, which may present with dermal and/or plexiform neurofibromas. Dermal neurofibromas are hormone-sensitive tumors that begin to appear as NF1 patients enter puberty, and these tumors have little to no malignant potential. Plexiform neurofibromas are often congenital, not hormone-responsive, and can undergo malignant transformation to MPNSTs.[16][17]

Clinical Significance

Guillain-Barre manifests clinically with symmetric ascending paralysis and paresthesia, which may progress to dyspnea and choking over hours to days. Management is supportive and, with ventilatory support and monitoring for cardiac arrhythmias and other complications, the prognosis is good with patients typically recovering function within 12 months.[13] The earlier the clinician identifies and treats the condition, the better the prognosis. In randomized controlled trials, there are two treatment options currently considered the standard of care in Guillain-Barre syndrome (GBS). These include either intravenous immunoglobulin (IVIG) or plasma exchange. IVIG is thought to act by its immune-modulating action however, the exact mechanism remains unclear. IVIG dosing is 2 grams/kilogram divided over 5 days.[18] [Level I] Plasma exchange is thought to act by removing pathogenic antibodies, humoral mediators, and complement proteins involved in the pathogenesis of GBS. Similar to IVIG, its exact mechanism of action in the treatment of GBS remains unproven. The patient generally receives plasma exchange as a volume of an exchange over five sessions.

Patients with CMT may present with distal muscle weakness, foot drop, depressed or absent deep tendon reflexes, atrophy of muscles of below the knee, and atrophy of the muscles of the thenar eminence. CMT does not reduce the lifespan, and management is supportive.[13][15]

Diabetic neuropathy classically arises in patients with long-standing diabetes as a sensory neuropathy with loss of temperature, vibration, touch, and pain sensation. Patients may also have accompanying neuropathic pain. Nerve damage progresses from small sensory fibers to large sensory fibers, to large motor fibers, causing weakness, loss of function, and paralysis. Nerve damage also is more pronounced in distal extremities, a characteristic &ldquostocking-glove&rdquo pattern. Treatment of diabetic neuropathy is limited to symptomatic treatment of neuropathic pain and maintenance of euglycemia to prevent the development of diabetic neuropathy or slow its progression.[2]

Schwann cell neoplasms can be identified by immunohistochemistry for Schwann cell markers such as S-100. Management varies from monitoring and supportive care for asymptomatic dermal neurofibromas to surgery, chemotherapy, and radiation for metastatic MPNSTs.[16][17][19][20]

Whats Carrying the Current in Neurons?

Ha! I've had the same question, and my conclusion was that they hadn't found out exactly how yet. But the web is increasing its reach, and when I googled my trawl dragged up this:

"Most science students can tell you that myelination speeds up action potentials as they move down an axon, but how does this work exactly? In my experience, the subject of myelination is not well taught in schools and so in this post I will try to provide a little bit more depth on the subject.

As most know, myelinated axons cause signals to travel via saltatory conduction. “Saltatory” comes from the Spanish verb “saltar” which means “to jump”. By wrapping around the axon segmentally, myelin leaves only small nodes open along an axon to which signals can “jump”, these nodes are called nodes of Ranvier. The question is now, are these signals really jumping? (hint… nope.)

Signals travel down an axon in two ways, electrotonic current spread and action potentials. Electrotonic current spread can be thought of as a flow of ions within the cellular fluid, mostly K+ and Na+. When Na+ flow into the axon via an action potential, it displaces other ions within the cytoplasm of the neuron causing them to move away from the location of the Na+ channels. This movement of charge is the basis of electrotonic current and it occurs very very quickly. For anyone who has done a physics class, it’s easy to recognize that particles at a temperature of 298K are moving fast, much faster than an ion channel can displace ions from the interstitial space into the cytosol.

It is for this reason that action potentials are actually very very slow in comparison to electrotonic current, so in order to increase conduction velocity down an axon we actually want to minimize the amount of time the signal is being transmitted as an action potential. It is exactly this that myelination accomplishes – the nodes of Ranvier are actually locations at which the signal is an action potential, and they are only necessary because electrotonic current decays over both time and distance. Action potentials are a necessary evil in this case. They refresh the signal, but actually slow down the rate of transmission as compared to an all-electrotonic axon.

Electrotonic current dissipates for two main reasons – loss of ions due to flow out of leak channels and also time. The farther an ion travels within the cytosol the higher the chances of it encountering a counter ion (Cl-), or having its path blocked by a cellular component. It is for these reasons that we need to introduce two variables for the calculation of conduction velocity, λ the length constant and τ the time constant. The length constant is the length over which the signal will decay below 37% of its initial value, and the time constant is the time required for a membrane to charge.

Conduction velocity is proportionate to the length constant over the time constant. This should be intuitive – signals which can travel electrotonically for a longer distance without decaying will travel faster. Additionally, membranes which require less time to change their charge will facilitate for faster charge movement.

By wrapping around the axon, myelin reduces the number of leak channels through which the ions can flow. This increases the length constant, the signal can thus travel further as electrotonic current and will therefore travel faster.

To conclude, myelin accelerates the rate of signal transduction down an axon for a variety of reasons. First, it decreases the number of leak channels along the axon, this causes ions to remain in the axon and allows signals to travel further as electrotonic current before needing to be refreshed as an action potential. The “jumping” referred to in the beginning of this post is actually the action potentials occuring along the axon and represents a renewing of the electrotonic current – they are a necessary evil and actually slow signal transmission. If there were less nodes of Ranvier then signals would actually travel faster (provided they didn’t die down below threshold). There is no actual jumping along the axon, all current is transmitted within the axon itself and is caused by ion flow."

[ Quoted from Anthony Isaacsons's blog without asking for permission, as it was posted for students of the subject my bold]

TLDR: Nodes of Ranvier acts like signal amplifiers along a long optic fiber cable.

My own confusion was from understanding nerve signal transmission as solely action potentials triggering massive scales of ion channel openings. (There is always a degree of random openings as "noise", due to the stochastic component of chemistry and hence of chemical machines.) But now I know.

Myelin sheath formation

In the peripheral nervous system (PNS), myelination is preceded by invasion of the nerve bundle by Schwann cells, rapid multiplication of these cells and segregation of the individual axons by Schwann cell processes. Smaller axons (≤1 μm), which will remain unmyelinated, are segregated several may be enclosed in one cell, each within its own pocket. Large axons (≥1 μm) destined for myelination are enclosed singly, one cell per axon per internode. These cells line up along the axons with intervals between them the intervals become the nodes of Ranvier.

Before myelination, the axon lies in an invagination of the Schwann cell (Figure 3). The plasmalemma of the Schwann cell then surrounds the axon and joins to form a double-membrane structure that communicates with the cell surface. This structure, called the mesaxon, elongates around the axon in a spiral fashion. Thus, formation of myelin topologically resembles rolling up a sleeping bag the mesaxon winds about the axon, and the cytoplasmic surfaces condense into a compact myelin sheath and form the major dense line. The two external surfaces form the myelin intraperiod line.

Myelin deposition in the peripheral nervous system (PNS) may result in a single axon having up to 100 myelin layers therefore, it is improbable that myelin is laid down by a simple rotation of the Schwann cell nucleus around the axon. In the central nervous system (CNS), such a postulate is precluded by the fact that one glial cell can myelinate several axons. During myelination, there are increases in the length of the internode, the diameter of the axon and the number of myelin layers. Myelin, therefore, expands in all planes at once. Any mechanism to account for this growth must assume that the membrane system is able to expand and contract and that layers slip over each other.

In the central nervous system (CNS), the structures of myelin are formed by the oligodendroglial cell 8) . This has many similarities but also points of difference with respect to myelination in the PNS. Central nervous system (CNS) nerve fibers are not separated by connective tissue, nor are they surrounded by cell cytoplasm, and specific glial nuclei are not obviously associated with particular myelinated fibers. Central nervous system (CNS) myelin is a spiral structure similar to peripheral nervous system (PNS) myelin it has an inner mesaxon and an outer mesaxon that ends in a loop, or tongue, of glial cytoplasm. Unlike the peripheral nerve, where the sheath is surrounded by Schwann cell cytoplasm, the cytoplasmic tongue in the central nervous system is restricted to a small portion of the sheath. This glial tongue is continuous with the plasma membrane of the oligodendroglial cell through slender processes. One glial cell can myelinate 40 or more separate axons 9) .

Figure 3. Formation of myelin sheath in the peripheral nervous system (PNS) – note that Schwann cell cytoplasm forms a ring both inside and outside of the myelin sheath.

Figure 4. Myelin sheath (the Schwann cell has surrounded the nerve axon)

Figure 5. Formation of myelin sheath in the central nervous system (CNS)

I'm trying to construct a single myelinated axon and I got confused with the pas mechanism.
1. If I use the pas mechanism for the biophysical part of the axon, then I'm constructing a myelinated axon?
2. NEURON constructs a myelinated axon by changing its electrical properties, so is there any way that I can specify the thickness of the myelin sheath? 3. If I want to construct a bare axon and see the effect of ion channels activity on action potential propagation, then I have to change the conductance of the ion channel(g) to zero instead of directly apply pas mechanism to the axon?

Thank you for taking the time reading my questions and I really appreciate your help.

Re: construct a single myelinated axon

Post by ted » Sun Oct 20, 2019 11:20 pm

Re: construct a single myelinated axon

Post by Sun Xiaoqing » Mon Oct 21, 2019 9:23 am

Thank you for your reply, Ted.

I'm constructing a single myelinated axon without any nodes, just a soma connected to myelinated axon to see how the AP propagates with the change of the diameter. I've looked into the extracellular in the Programmer's reference and I also found there was an extracellular pannel in the section of Biophysics of the cell builder. And I still have some trouble understanding it.

1. In the cell builder/Biophysics/extracellular, xraxial xg xc refers to the electrical parameters of the myelin sheath, but I didn't understand what's the meaning of xraxial[1] xg[1] xc[1]. In my case, I don't need to consider this second layer?

In order to choose the correct parameters for xraxial xg xc and e_extracellular =?I tried to use the parameters in the topic:viewtopic.php?f=8&t=1814&p=6589&hilit=m . eath#p6589
which is for internodal sections: insert extracellular xraxial=1e9 xg=0 xc=0 e_extracellular=0.
Why xc is set to be 0? Myelin sheath and membrane can't be considered to have capacitance?

2. I use d_lambda rule for all my sections (soma and axon), and the length of the axon L=1000um, but the number of segment=1. So if I set the n_seg manually (e.g. 10), is that going to affect my simulation results?

3. If I use the parameters:

, it can genreate AP. Maybe this problem was due to the previous steps and misunderstandings.

4. The last question is that if I use the cell builder to construct my axon then apply the extracellular mechanism, the diameter I defined in the geometry section is actually the total fiber diameter(including myelin sheath), is that right? Also, if I change the diameter, it will change the electrical properties of the myelinated axon, I don't need to change xraxial xg xc accordingly, right?

Sorry for the plenty of questions and such a long reply, thank you so much for taking the time to read my questions.

Re: construct a single myelinated axon

Post by ted » Mon Oct 21, 2019 9:49 am

Re: construct a single myelinated axon

Post by Sun Xiaoqing » Tue Oct 22, 2019 4:10 am

Thank you for your answer, ted.

So if I use extracellular to construct myelinated axon(even with nodes of Ranvier), then I won't be able to see the spike along the myelinated axon at the internode sections(which I tried and the voltage remained to -65mV), I could only get the AP configuration at the nodes of Ranvier, is my understanding correct?Why I the voltage at the internode section(myelinated axon remained -65mV?) Was that due to the errors in the code?

If I want to see the Spike Configuration along the myelinated axon, then I couldn't use Extracellular, I have to reduce the capacitance of the axon mannualylike what J W Moore did in Conduction in uniform myelinated axons (Moore et al 1978): . 851#tabs-1 and Brill in Myelinated axon conduction velocity . 848#tabs-1,right?

Thanks again for your patient reply to my relative basic questions, really appreciated it!

Re: construct a single myelinated axon

Post by ted » Tue Oct 22, 2019 9:43 am

Transmembrane potential will change only if the charge stored on membrane capacitance changes. That requires transmembrane current to flow. The insulating effect of myelin reduces the amount of membrane current that can flow. That's why you don't see much of a change of v in the internodes.

If you build a model of myelinated axon but don't use extracellular, then your model gives you no way to discover the voltage across the axonal membrane (the difference between electrical potential inside the axon and just outside the axon membrane). Instead, v in the internode will represent the sum of axonal membrane potential and the voltage drop across the myelin sheath.

Re: construct a single myelinated axon

Post by Sun Xiaoqing » Tue Oct 22, 2019 10:31 am

1. I understood that if myelin sheath is wrapped around the axon, the voltage-gated ion channels in the axolemma couldn't get participated in the process of an AP generation and there're no transmembrane currents. Since no transmembrane currents were involved during Propagation, no spike configuration could be observed.

2. If I use extracellular to construct myelinated axon, the voltage I got at any specific position along the internode section(e.g.myelin[0].v(0.1)) remained to -65mV(the difference between electrical potential inside the axon and just outside the axon membrane) wouldn't change due to no transmembrane currents.

3. For the work done by Brill and Moore, they used pas mechanism and reducing the capacitance of the axon to construct myelinated axon, the spike configuration occurred was the voltage difference between the sum of axonal membrane potential and the voltage drop across the myelin sheath.
Is my current understanding correct? Thank you.

So if I want to see the spike propagation along a myelinated axon, can I refer to the work done(the effect of changing the diameter of the axon on the capacitance) by Moore using pas instead of extracellular

Referring back to the parameter table provided in the paper . 0-0047.pdf, Axon Diameter(internal) is 10um, and the myelin thickness is 2um, I wonder why for the myelin section, the diameter was set to be 10um instead of 12um.

Also in the paper it stated that

which is obtained by simply dividing the specific membrane capacitance by a factor of 200 layers.
So the myelin capacitance and conductance were specified relative to the inner diameter (10 um) of the axon, I wonder if this is the reason why NEURON chose diam=10um for the myelin section.

I hope maybe you can shed some light on my confusion. Thank you as always.

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