Describe Continuous Conduction Compare and Contrast It With Saltatory Conduction

Saltatory Conduction

Saltatory conduction describes the way an electrical impulse skips from node to node down the full length of an axon, speeding the arrival of the impulse at the nerve terminal in comparison with the slower continuous progression of depolarization spreading down an unmyelinated axon.

From: Encyclopedia of Neuroscience , 2009

Peripheral Nervous System Topics

Enrico Marani , Egbert A.J.F. Lakke , in The Human Nervous System (Third Edition), 2012

Schwann Cells at the Node of Ranvier

For the saltatory conduction myelin is a necessary prerequisite. The myelin areas near the node of Ranvier are subdivided in intermodal, juxtaparanodal and paranodal areas (Figures 4.19, 4.20). The naked axonal area is the nodal area. The nodal area contains sodium channels, the juxta- and paranodal area are mainly characterized by potassium channels (Figure 4.20; Waxmann and Ritchie, 1993). The coverage by myelin of the potassium channels suggests that saltatory guidance is an exclusive sodium channel concern. The paranodal loops and junctions are covered with Caspr (rat contactin-associated protein), while the microvilli contain ERM proteins (ezrin, radixin, and moesin) (Melendez-Vasquez et al., 2001). The nodal axolemma is characterized by ankyrin binding. Indeed at the axolemma binding near the end of the paranodal and microvilli areas, also-called axon initial segment, Ig/FNIII family (that uses ankyrin binding) adhesion molecules were demonstrated (Davis et al., 1996, Bhat et al., 2001). The paranodal junctions function for: anchoring to the axon, making an ion diffusion barrier, and producing a physical barrier producing distinct axonal compartments (Bath et al., 2001).

FIGURE 4.19. Axon initial segment at the nodal area with coupling proteins.

Reproduced from Melendez-Vasquez et al., 2001.

FIGURE 4.20. Distribution of sodium and potassium channel isoform types Na_v1.6, Na_v1.3, K_v1.1 and K_v1.2 at the node of Ranvier.

Reproduced with permission from E.A.J.F. Lakke.

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Na+ Channel Reorganization in Demyelinated Axons

Peter Shrager Ph.D. , ... Katia Kazarinova-Noyes Ph.D. , in Multiple Sclerosis As A Neuronal Disease, 2005

I. Consequences of Demyelination

The concept of saltatory conduction, first defined more than 50 years ago ( Tasaki and Takeuchi, 1942; Huxley and Stampfli, 1949), firmly established the fact that in normal myelinated axons, inward current through sodium (Na⁺) channels occurs uniquely at nodes of Ranvier. Correspondingly, voltage clamp experiments, first on amphibian axons and later on mammalian fibers, demonstrated directly that there is a high density of Na⁺ channels at these sites (Dodge and Frankenhaeuser, 1959; Chiu et al., 1979). At issue, however, was the possible expression of these channels within internodal regions as well. Na⁺ channels under myelin are not likely to be activated during action potential propagation, or under voltage clamp, because they would see only a fraction of the resulting depolarization. Thus, other approaches were required to establish with certainty the distribution of these channels. This information is important both to define the steps that neurons must follow during development and because it has functional consequences in demyelinating disease. Some early experiments provided important clues. Nodal regions were found to have biochemically distinct cytoplasmic surfaces, suggesting unique cytoskeletal components (Quick and Waxman, 1977). The more recent demonstration of a specific adapter protein (ankyrin_G) and a spectrin isoform (βIV) localized to nodes and initial segments confirms this idea (Kordeli et al., 1995; Berghs et al., 2000; Komada and Soriano, 2002). Freeze-fracture replicas demonstrated high densities of large intramembranous particles in both the node and juxtaparanode, and much lower densities in theaxoglial junction region of the paranode and in the remainder of the internode (Rosenbluth, 1976, 1981). The densities of these particles in the nodal gap (∼1,300/μm²) agree with biophysical estimates of Na⁺ channel density (1,000–1,500/μm²; reviewed in Hille, (2001). This work suggested a specific clustering of Na⁺ channels at nodes and initial segments, but left open the possibility of a lower density within internodes.

Direct electrical measurements provide the most sensitive method of detecting voltage-dependent channels. Two groups studied gap-voltage-clamped internodes acutely exposed to lysolecithin to disrupt myelin. Voltage-dependent Na⁺ and potassium (K⁺) currents could be recorded concomitant with an increase in membrane capacitance. Grissmer (1986) found the internodal Na⁺ current density to be only 0.2% of the nodal level. Chiu and Schwarz (1987) measured this ratio to be about 3%, but considered the possibility that the recorded Na⁺ currents originated from Schwann cell membranes fused to the axolemma by lysolecithin. Schwann cells in vitro express voltage-dependent Na⁺ channels (Chiu et al., 1984; Shrager et al., 1985). However, it was later shown that, in vivo, these channels are restricted to nonmyelinating Schwann cells (Wilson and Chiu, 1990; Chiu, 1993).

Studies on axons demyelinated in vivo provided more details. Hall and Gregson (1971) introduced a method for focal demyelination that reproduces many aspects of inflammatory demyelinating disease and can be used in amphibian and mammalian species. A small amount of lysolecithin (1 μl, 1% in adult sciatic nerve) is injected surgically directly into a nerve trunk and the animal is allowed to recover. The drug vesiculates the outmost layers of myelin, which initiates an inflammatory response, with macrophages entering the lesion from the blood and removing myelin debris by phagocytosis. Affected internodes are completely stripped of myelin, a process that is completed by 1 week postinjection. At this time, if the nerve is dissected and teased, axons can be found that are devoid of all glial membranes and are surrounded only by a disrupted basal lamina. If the animal is allowed to recover for longer periods, Schwann cells proliferate and begin the process of remyelination (Shrager and Rubinstein, 1990). In the rat sciatic nerve, the earliest signs of repair are seen at about 9 days postinjection, and by 14 days many fibers have thin sheaths of new myelin. In the mouse, all events are speeded by 1 to 2 days. Working with both Xenopus and rat sciatic axons, Shrager recorded Na⁺ currents with the loose patch clamp (Fig. 1) and found an internodal density about 4% of the nodal value (Shrager, 1987, 1988, 1989). Measurements could be made as early as 1 day postinjection, by applying suction to allow the patch pipette to advance through the myelin debris and seal to the axolemma. The internodal density was constant during 2 months postinjection, suggesting that these channels are not introduced as a result of the demyelination.

Figure 1. Ionic currents recorded from a rat sciatic demyelinated internode with a loose patch clamp pipette. The membrane potential was held 30 mV negative to the resting value and was depolarized by pulses of 40, 60, 70, 80, 90, and 110 mV This nerve was 3 days postinjection.

(Reprinted from Brain Research [Shrager, 1989], copyright 1989, with permission from Elsevier.)

The measurement also agreed well with that of the acute experiments of Chiu and Schwarz (1987). Since the nodal density of Na⁺ channels is about 1,000–1,500/μm², the internodal density is 40–60/μm². This latter figure is significant for two reasons. First, it is close to the value expected for nonmyelinated axons of similar caliber. Thus, in principle, it could support conduction. Second, although it represents only a few percent of the nodal density, since the internodal surface area is about 1,000 times that of nodes, it suggests that more than 95% of the axonal Na⁺ channels are internodal. Therefore, they constitute a large pool of channels that may be used in repair or replacement. When axons (both peripheral [PNS] and central nervous systems [CNS]) remyelinate they typically form several short internodes within a single previous internodal region. The gaps between these short internodes must function as nodes if saltatory conduction is to be successful through this zone, and they must therefore obtain a high density of Na⁺ channels from some source. These channels may be synthesized de novo in the soma and transported down the fiber, or they may be recruited from the internodal pool.

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Glial Cell Development

Laura Fontenas , Sarah Kucenas , in Reference Module in Life Sciences, 2017

SCs and Establishment of the Nodes of Ranvier

Nodes of Ranvier are at the core of saltatory conduction along myelinated axons ( Fig. 1(d)). They contain all of the molecular machinery responsible for the propagation of action potentials along myelinated nerves (Black et al., 1990). If myelin is necessary for the fast propagation of action potentials by insulating the axons, the nodes of Ranvier are all the more important for this purpose as they regenerate the action potentials along their entire course by allowing current to enter the axolemma through voltage-gated sodium channels (Black et al., 2002). Although the components of the nodes are well established, the molecular mechanisms that give the nodes their functional organization in vivo have remained poorly understood until recently. Investigations in zebrafish have defined a number of proteins involved in node of Ranvier formation and function. A study showed the requirement of the N-ethylmaleimide sensitive factor (NSF), a key protein involved in membrane fusion, for node of Ranvier organization along myelinated axons (Pogoda et al., 2006; Woods et al., 2006). This study, involving a neuronal factor, highlights the crucial dialog between neurons and their associated glia, which are required for the proper organization of myelinated axons and is consistent with a previous study conducted in rat (Vabnick et al., 1996). This report also demonstrated that neuronal activity and PNS myelination is different from the CNS, as elimination of action potentials or synaptic release does not affect myelin gene expression nor node of Ranvier organization (Woods et al., 2006).

It has always been an intriguing question whether myelin is responsible for creation of nodes or, if on the contrary, nodes are responsible for the shape of the myelin internodes (Fig. 1(d)). A report shed light on this mystery by demonstrating that in numerous mutants lacking SCs (e.g., erbb2, erbb3, sox10/cls), a significant number of aberrant clusters of sodium channels were distributed all along peripheral axons, suggesting that SCs control sodium channel clustering (Voas et al., 2009). In gpr126 mutants, where SCs are arrested at the promyelinating stage, a significant decrease in the number of clusters could be seen in comparison to embryos lacking SCs, but clustering still existed. Taken together, these data show how important the interaction between neurons and glia are for axonal organization.

Many studies have contributed to enrich our understanding of peripheral myelination and have revealed key genes and proteins involved in SC migration, differentiation, and in the initiation of myelination. Additionally, different behaviors of SCs have been observed depending on the nerve they are associated with. These differences now raise a new question. Do SCs that associate with the sensory and motor nerves really have the same identity? Future studies will be needed to dissect whether these two subpopulations are molecularly and functionally distinct.

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Paracellular Channel in Organ System

Jianghui Hou , in The Paracellular Channel, 2019

7.3.1 Autotypic Tight Junction

The ensheathment of neurons with the myelin enables rapid saltatory conduction of action potentials in the nervous system. To facilitate this process, the intramyelinic space must be sealed by TJs to prevent electric current leakage. Peters first observed a radial component in the intraperiod line that appeared as rod-like thickening under transmission electron microscopy and hypothesized it to be the TJ ( Peters, 1961; Peters, 1964). Freeze fracture replica electron microscopy revealed linear intramembranous strands of ∼10 nm in diameter between the myelin lamellae and resembling the TJ structure found in epithelial or endothelial cells (Dermietzel, Leibstein, & Schunke, 1980; Reale, Luciano, & Spitznas, 1975). This type of TJ is formed by one cell, for example, the oligodendrocyte in the central nervous system (CNS) or the Schwann cell in the peripheral nervous system (PNS), and termed as autotypic TJ. The autotypic TJ seals the intramyelinic space and provides electrical insulation to the myelinated axon (Fig. 7.22).

Figure 7.22. Schematic diagram of an axon ensheathed by the myelin lamellae.

A simplified model unravels the myelin as membrane sheets spiraling around the axon (top). The cross-section view reveals the key features of the myelin including the major dense line and the intramyelinic space, which are organized into the myelin period (bottom). Current flow (green arrow) into the intramyelinic space is normally blocked by the autotypic TJ (green dot).

(Reproduced with permission from Gow, A., & Devaux, J. (2008). A model of tight junction function in central nervous system myelinated axons. Neuron Glia Biology, 4, 307–317)

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Demyelinating Disorders of the Central Nervous System

Istvan Pirko , John H. Noseworthy , in Textbook of Clinical Neurology (Third Edition), 2007

ROLE OF MYELIN

Myelin provides insulation for axons and is necessary for saltatory conduction. It is composed of tightly wrapped lipid bilayers with specialized protein constituents. Peripheral nervous system (PNS) myelin is formed by the extension of Schwann cells, and central nervous system (CNS) myelin is produced by oligodendrocytes. The myelin coating is interrupted at regular intervals (nodes of Ranvier) where the axon membrane with its concentration of voltage‐gated sodium channels is exposed to the extracellular environment ( Fig. 48‐1). ⁵ The presence of myelin is essential to maintain conduction velocity; its loss or damage can lead to significantly slower conduction or conduction block. Other factors affect conduction velocity including certain antibodies and chemicals like nitric oxide. In certain cases, blockade may be the initial event in the cascade of events leading to demyelination.

CNS and PNS myelin differ in a number of important ways. Schwann cells myelinate only one internodal segment from a single PNS axon, whereas oligodendrocytes myelinate multiple CNS axons. The proteins also differ. Proteolipid protein (PLP) accounts for approximately 50% of the CNS myelin proteins. Mutations in this highly conserved protein cause Pelizaeus‐Merzbacher disease. Protein zero is the major PNS myelin protein and performs a function similar to PLP in compacting the intraperiod line. Myelin basic protein (MBP) makes up 30% of CNS and 10% of PNS myelin proteins. MBP is not an integral protein but binds to the cytoplasmic surface and is responsible for compaction at the major dense line. Myelin associate glycoprotein accounts for about 1% of both peripheral and central myelin. Myelin oligodendrocyte glycoprotein and cyclic nucleotide phosphodiesterase are minor constituents of CNS myelin and are not found in the PNS. Peripheral myelin protein 22 is a minor component of PNS myelin.

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Myelination

UELI SUTER , RUDOLF MARTINI , in Peripheral Neuropathy (Fourth Edition), 2005

Establishing the Myelin Internode

Myelination is a pivotal prerequisite for the rapid and saltatory conduction of action potentials, but also for the maintenance of the axonal structure. ¹⁰⁹ Two principle myelinating glial cells are found in the nervous system of higher vertebrates, the oligodendrocytes in the central nervous system (CNS) and the Schwann cells in the peripheral nervous system (PNS).

Being predominantly derivatives of the neural crest, ^{75, 90, 127} embryonic Schwann cells travel along axon bundles during development. ^{16, 17} These cells are most probably Schwann cell precursors, that is, prospective Schwann cells that still lack the ability to survive in the absence of axons. ¹¹⁷ In the rat, Schwann cell precursors have been identified up to embryonic days 14 and 15 and do not yet express significant levels of the glial marker S100. Surprisingly, only scant attention has been paid so far to the morphologic characteristics and developmental changes of these cells, although they have been viewed as pivotal cellular components for axon survival. ¹⁴⁸ A role in guiding axons to their targets during development has been proposed earlier. ¹²⁰ This appears less probable because, during development, Schwann cell precursors follow pioneer axons in the embryo. ^{16, 17, 154} In addition, Schwann cell precursors cannot survive when contact with axons is precluded, ¹¹⁷ and axons find their targets in the absence of Schwann cell precursors. ¹⁴⁸

Schwann cell precursor cells are characteristically devoid of a basal lamina, intermingling and extending processes between the axon bundles (Fig. 19-1A). These cells are additionally found at the margin of the prospective nerve, facing the mesenchyme with their abaxonal surface (Fig. 19-1A). ^{12, 17, 34, 35, 108, 135, 209}

When development proceeds, Schwann cell precursors start to form a basal lamina, proliferate, and collectively ensheathe fasciculating axons, forming so-called Schwann cell families as initially described by Webster and colleagues. ^{136, 195} By then such glial cells most probably have reached the stage of immature Schwann cells, a term characterized by the ability to survive independently as a result of an autocrine survival mechanism. ^{99, 117} In the rat, all glial cells of the sciatic nerve are immature Schwann cells by embryonic day 17, whereas in the mouse, immature Schwann cells are the main population by embryonic day 15. ^{43, 117}

The next step in development is related to an increase in caliber of some axons before becoming myelinated. They acquire a "peripheral" position within the axon bundles and achieve a so-called 1:1 ratio with immature Schwann cells (Fig. 19-1B). This stage of Schwann cell development is called "promyelin," a morphologic starting point for myelin formation. In rodents, this sorting of many larger caliber axons into the promyelin stage occurs at around birth. However, myelin formation in the PNS is not a highly synchronized event. Axons with large calibers become myelinated earlier than those with smaller diameters, so that some promyelin stages can still be found in mice of approximately 3 weeks of age.

The promyelin stage is followed by spiral formation of one of the Schwann cell processes engulfing the axon (Fig. 19-2; see also Fig. 19-1B). The apposition of Schwann cell membranes at the inner, axon-related side of the Schwann cell process is called the "inner mesaxon," whereas the contact of Schwann cell membranes at the endoneurial side is termed the "outer mesaxon" (Fig. 19-2). These cell contacts are characterized by the formation of adherens (desmosomelike) junctions (Fig. 19-2). In an elegant study, Bunge and colleagues ²⁵ investigated the question of which end of the Schwann cell, the inner or outer one, turns around the axon during myelination. For this purpose, living rat Schwann cells co-cultured with dorsal root ganglion neurons were first investigated at the light microscopic level and the movements of the Schwann cell nuclei were recorded. After having monitored the behavior of the Schwann cells for up to 70 hours, the cultures were fixed and the axon–Schwann cell units in question were examined by electron microscopy (Fig. 19-3). These studies revealed that it is basically the inner, axon-related Schwann cell process that turns around the axon, and that the cell soma containing the nucleus is dragged behind at a much slower rate than the inner lip of the axon-related end of the Schwann cell process. This view is in line with older models stating that insertion of myelin components (e.g., radiolabeled lipids) ¹³⁶ occurs along the entire extension of the developing spiral. Thus relatively rapid turning of the inner lip of a relatively slow-moving Schwann cell body and the simultaneous overall insertion of myelin membrane components appear to be characteristic events during myelin formation in the PNS.

In vivo studies revealed that the myelinating process appears more complicated than just a spiral formation of the inner Schwann cell process around the axon. For instance, irregular forms with thin, redundant myelin loops are often observed (see Fig. 19-1B). In addition, the myelinating process in the region of the Schwann cell nucleus turns at a higher rate around the axon than the same process at the level of the Schwann cell edges (i.e., near the prospective node of Ranvier). A comprehensive overview of the morphologic events during myelin formation is summarized by Webster and colleagues. ^{136, 195}

A unique subcellular feature of myelinating glial cells is the compaction of the turning membranes. In the case of rodent Schwann cells, this occurs when the myelinating process has turned around the axon a few times. Two processes occur simultaneously: (1) the narrowing of the spiraling surface membranes from approximately 12 to approximately 2 nm, and (2) the "squeezing out" of cytoplasm. The collapsed cytoplasmic sites of the Schwann cell membranes fuse and form a 3.5-nm-wide electron-dense band called the "major dense line"; the membrane leaflets facing the extracellular space of the spiral form the "intraperiod line," which is double-layered as a result of the 2-nm gap separating the extracellular leaflets (see Fig. 19-2B). ¹³⁶

Immature myelin sheaths are characterized by relatively expanded sites of still uncompacted myelin containing cytoplasm. During maturation, however, uncompacted myelin becomes restricted to distinct sites, such as the periaxonal collar (see Fig. 19-2), the outer Schwann cell loop, the paranodal loops, and the Schmidt-Lanterman incisures. The latter are funnel-like clefts traversing the internodal myelin sheath and forming a helical cytoplasmic band that connects the periaxonal with the perinuclear (abaxonal) Schwann cell cytoplasm. In longitudinal sections of osmium tetroxide– fixed tissue, they can be identified on light microscopy as slim, bright lines obliquely traversing the myelin. In teased fiber preparations labeled for markers of noncompacted myelin (e.g., myelin-associated glycoprotein [MAG], connexin 32 [Cx32]), Schmidt-Lanterman incisures appear as funnel-like profiles. ^{5, 6, 159} Electron microscopy reveals that they consist of slender pockets of cytoplasm that form a helical funnel. Based on the observation that these cytoplasmic domains are Cx32 positive, it has been speculated that they form a rapid, radial cytoplasmic pathway for ions and small molecules between the adaxonal and abaxonal Schwann cell cytoplasm. ¹⁶⁰ Interestingly, recent immunohistochemical studies on teased fiber preparations revealed that Caspr1/paranodin and the voltage-gated K⁺ channels Kv1.1 and 1.2 demarcate the axonal domain underlying the inner loop of the Schmidt-Lanterman incisures. ^{5, 6, 159}

An interesting question is the regulation of myelin thickness. In particular, a striking feature is the positive correlation between axonal caliber and myelin thickness. This is clearly reflected by the observation that the quotient between axon diameter and fiber diameter (taken at the outer aspect of the myelin sheath) is generally constant when axons of different diameters are compared. ⁶⁴ A similarly constant interrelationship exists between internodal length and axon diameter in the adult nerve. Quantitative studies in various species have revealed that a normal internode of a mature peripheral nerve is usually 100 times as long as the diameter of the corresponding axon. ⁶⁴ However, developmental studies in nerves with a robust growth in length during maturation in the absence of Schwann cell proliferation modified this simple view, as revealed by studies in phrenic nerves in rabbits and several peripheral nerves in humans. ^{64, 165} In young rabbits, myelin sheaths are relatively thin for axon diameter, followed by an increase in myelin thickness. ⁶⁴ An extreme case is found in various human peripheral nerves. Although radial growth of axons is completed at 5 years of age, the corresponding myelin continues to grow in thickness until the age of 17. ¹⁶⁵ In tibial nerves of rats, maximal growth in axonal diameter occurs between 3 weeks and 3 months. Here, the developmental change in relative myelin thickness is not uniform because myelin sheaths of fibers of different caliber behave in a slightly different way during development. ⁶⁰

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Peripheral Nerve Disorders

Grahame J. Kidd , ... Bruce D. Trapp , in Handbook of Clinical Neurology, 2013

Nonmyelinating (remak) Schwann cells

Biophysical calculations indicate that the electrophysiological benefits of myelination and saltatory conduction decrease as axonal diameter is reduced and that there is no velocity advantage compared with continuous conduction for axons smaller than around 1  μm in diameter. In humans, three-quarters of mature axons in the PNS are at or below this size and unmyelinated (Ochoa and Mair, 1969). They are ensheathed by nonmyelinating Schwann cells. The main populations of axons surrounded by nonmyelinating Schwann cells are the small nociceptive (C-type) axons, and the postganglionic sympathetic axons, and some of the preganglionic sympathetic and parasympathetic fibers. Many pre- and postganglionic axons of the autonomic nervous system are unmyelinated for their entire lengths. In addition, all PNS axons are unmyelinated for some of their length, specifically at regions proximal to neuromuscular junctions, at the most distal segments of sensory and autonomic neurons, and specialized sensory endings of the Pacinian and Meisner's corpuscles. Most unmyelinated axon segments are surrounded by Schwann cells: the exception is where C fibers enter into the epidermis and lose Schwann cell associations to become free nerve endings (Hsieh et al., 1994). Within the neuromuscular junction, nonmyelinating Schwann cells cover the exposed axonal surface but do not surround the axon where it apposes the neuromuscular junction. In this way the Schwann cell basal lamina does not intervene between the synaptically active axon surface and the muscle, but rather the Schwann cell basal lamina merges with that of the muscle fiber (Griffin and Thompson, 2008). Schwann cells that are orphaned following axon and myelin degeneration in injury or neuropathy also constitute a population of nonmyelinating Schwann cells. Satellite cells, which surround sensory and autonomic neurons in the peripheral ganglia may also represent a form of nonmyelinating Schwann cell (see Peters et al., 1991).

Within nerves, unmyelinated axon–Schwann cell units are termed Remak fibers and in transverse section, each unit includes a single Schwann cell and usually multiple axons (Fig. 5.10A) (see review by Griffin and Thompson, 2008). Remak Schwann cells have territories that extend longitudinally for 50−100   μm (Aguayo et al., 1976a; Thomas et al., 1993) (Fig. 5.10B ). Schwann cells envelop the axons within troughs on their surface (cytoplasm. In smaller Figs. 2 and 10A). Consequently, the axons also reside inside the Schwann cell basal lamina. Occasional axons may be incompletely surrounded by the Schwann cell processes (Fig. 5.10A), including some that lie directly beneath the Schwann cell basal lamina. Unmyelinated axons exchange frequently among different Remak bundles as they extend along the nerve (Fig. 5.10C) (Aguayo et al., 1976a; Murinson et al., 2005b) such that the same axons are unlikely to lie adjacent to each other for a significant length. A single Remak Schwann cell can ensheath different kinds of axons, including mixes of sensory and autonomic axons. Individual Remak Schwann cells may likewise associate with axons arising from different spinal nerves ("polyradicular ensheathment") (Murinson et al., 2005b). How the mixed axons are sorted back into dermatomal distributions is unclear, but probably reflects axon outgrowth patterns early in development (Griffin and Thompson, 2008). Another implication of Remak fibers bearing multiple types of axons is that different axons in the same Remak fiber may have multiple adhesion properties.

Fig. 5.10. Nonmyelinating Schwann cells. (A) By EM most unmyelinated axons in mouse dorsal roots are surrounded by Schwann cells (arrowheads). (B) Serial sectioning analysis of Remak fiber illustrates the irregular surface contours of nonmyelinating Schwann cells (nucleus N₁). (C) Individual axons can transition from one Remark bundle (N₁) to another (N₂). (D) In L1-deficient dorsal roots many unmyelinated axons are not surrounded by Schwann cells (arrow). Ax, axon; Nu, nucleus.

(A,D: Reproduced with permission from Haney et al. (1999); B,C: from Aguayo et al. (1976a).)

By definition, nonmyelinating Remak Schwann cells are characterized by the lack of myelin and myelin component expression, but they also characteristically express cell adhesion molecules and cell surface receptors that are downregulated on myelinating cells (for review see Mirsky et al., 2008), and may contribute to Remak Schwann cell function. The cell adhesion molecules L1 and N-CAM are both downregulated during early stages of myelination. In transgenic L1-deficient sensory nerves, Schwann cells formed normal unmyelinated axonal ensheathments but failed to retain them (Haney et al., 1999) (Fig. 5.10D), while sympathetic nerves were unaffected. Cross anastomosis experiments demonstrated that L1 expression by Schwann cells was essential for sensory axon−Schwann cell contact and axonal survival. N-CAM is a 120−180   kDa glycoprotein involved in axonal outgrowth (see review by Martini, 1994). N-CAM loss from Schwann cells, however, appears to have little impact on axon   −   Schwann cell interactions (Moscoso et al., 1998). Schwann cells also express p75, the low affinity NGF receptor, which is important for developing and regenerating motor neurons (Tomita et al., 2007), although it may play other roles. Nonmyelinating Schwann cells also express glial fibrillary acid protein (GFAP), and its loss in transgenic mice resulted in impaired remyelination (Triolo et al., 2006).

In addition to growth factor production in demyelination and remyelination (discussed below) the intimate relationship between nonmyelinating Schwann cells and axons suggests specific functions in axonal maintenance. Studies by Robert and Jirounek (1994) indicate that nonmyelinating Schwann cells do participate significantly in K⁺ sequestration, and so contribute to maintaining the immediate periaxonal ionic microenvironment. Radiolabeling studies of glucose metabolism suggest that 75% of the glucose uptake in Remak fibers occurs directly into the Schwann cells (Vega et al., 2003), which in turn provide lactate to the axons (Vega et al., 1998), as described for CNS astrocytes. In PN in which Schwann cell mitochondria were experimentally compromised (Viader et al., 2011), small fiber loss occurred before myelinated fibers. This suggests that unmyelinated axons may be critically dependent on Schwann cell metabolites, or that they are dependent on Schwann cells performing an energy-demanding function. Another important function of Remak Schwann cells is as a reservoir of potentially mitotic cells. Remak cells retain the capacity to undergo mitosis in mature nerve even while associated with unmyelinated axons (Murinson et al., 2005a), and are prompted to divide by local myelin damage. Given that PNs are vulnerable to damage, such a source of new cells for nerve repair and remyelination may be critical.

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Functional Neural Transplantation IV

Natalia A. Murphy , Robin J.M. Franklin , in Progress in Brain Research, 2017

2.4 Remyelination: The Default Response to a Demyelinating Insult

In response to demyelination, the adult CNS regenerates myelin sheaths restoring saltatory conduction ( Smith et al., 1979) and reversing functional deficits (Duncan et al., 2009; Jeffery and Blakemore, 1997; Liebetanz and Merkler, 2006) in a process called remyelination (Fig. 1). This is a unique example of regeneration in an otherwise poorly regenerating CNS and is the default outcome in both experimental models of demyelination and in naturally occurring CNS diseases, including those of humans (Lasiene et al., 2008; Patrikios et al., 2006; Smith and Jeffery, 2006). Remyelination is achieved by OPCs, and broadly follows the principles of developmental myelination, with some exceptions (Fancy et al., 2011a).

Fig. 1. Remyelination in the central nervous system. The diagram shows a simplified scheme of white matter remyelination in the mammalian CNS, along with cross-sectional images of a myelinated, demyelinated, and remyelinated white matter tract, stained with toluidine blue to visualize myelin. Myelinated white matter tracts contain directionally aligned axonal fibers myelinated by oligodendrocytes (purple), and a widespread population of OPCs (blue) (A). Other cells present (microglia and astrocytes) have been omitted for clarity. Insult to oligodendrocytes or the myelin itself leads to demyelination—leaving axons denuded (B). In response to this remyelination ensues. Resident OPCs migrate to the lesion site and proliferate in the first phase of remyelination called recruitment (C). Subsequently, the OPCs differentiate into oligodendrocytes (D), which establish contact with axons in order to ensheath them with myelin. These newly formed oligodendrocytes recreate the myelin sheaths (E), which are significantly thinner than the original sheaths, but nonetheless restore saltatory conduction and reverse any functional deficits which arise due to demyelination.

In response to myelin and oligodendrocyte damage, resident astrocytes and microglia produce factors which initiate the inflammatory response and activate OPCs within and around the damaged area. Activated OPCs undergo a change in morphology (Levine and Reynolds, 1999), upregulate specific activation genes, reexpress developmental markers (Fancy et al., 2004; Moyon et al., 2015; Watanabe et al., 2004), and become more responsive to mitogens produced by surrounding cells (Hinks and Franklin, 1999).

Using environmental cues, activated OPCs proliferate and migrate into and within the lesion. This constitutes the recruitment phase of remyelination. In the next phase of remyelination, OPCs exit the cell cycle and differentiate into oligodendrocytes. These cells establish contact with denuded axons, and extend cytoplasmic processes, which wrap around them and form a compact myelin sheath. Apart from the smallest diameter myelinated axons, remyelinated axons are characterized by a thinner myelin sheath relative to their diameter (i.e., higher g ratio). The functional significance of this finding is currently unknown. The g ratio appears to be unchanged if the remyelination is carried out by SVZ-derived OPCs, although this may be due to the small diameter of the axons of the corpus callosum (Stidworthy et al., 2003).

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Electrodiagnostic Findings in Neuromuscular Disorders

Bashar Katirji M.D., F.A.C.P. , in Electromyography in Clinical Practice (Second Edition), 2007

Demyelinating Polyneuropathies

The electrophysiologic hallmark of these polyneuropathies is a widespread increase in conduction time due to impaired saltatory conduction. Hence, the NCSs are characterized by significant slowing of conduction velocities (<75% of lower limit of normal) and distal latencies (>130% of upper limit of normal).

With distal stimulation, the CMAP amplitude is mildly or moderately reduced because of abnormal temporal dispersion and phase cancellation, and the distal latency is delayed because of demyelination. With more proximal stimulation, the CMAP amplitude is lower due to temporal dispersion and conduction block along some fibers. The proximal conduction velocity is markedly slowed because of increased probability for the nerve action potentials to pass through demyelinated segments (Figure 4-10C).

Chronic demyelinating polyneuropathies may be further distinguished by NCS into inherited and acquired polyneuropathies. Inherited demyelinating polyneuropathies such as Charcot-Marie-Tooth disease type I, are characterized by uniform slowing along various segments of individual nerves and adjoining nerves. The abnormalities are usually symmetrical without accompanying conduction blocks (except possibly at compressive sites). In contrast, acquired demyelinating polyneuropathies, such as chronic inflammatory demyelinating polyneuropathy, often have asymmetric nerve conductions, even when there is no apparent clinical asymmetry. In addition, multifocal conduction blocks and excessive temporal dispersions at nonentrapment sites are characteristics for acquired demyelinating polyneuropathies.

In demyelinating polyneuropathies, the needle EMG may show signs of mild axonal loss manifested by fibrillation potentials and reinnervated MUAPs.

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Growth Factors in Development

Alya R. Raphael , William S. Talbot , in Current Topics in Developmental Biology, 2011

1 Introduction

The myelin sheath increases axonal conduction velocity by reducing capacitance of the axonal membrane and allowing saltatory conduction ( Hodgkin, 1964; Stampfli, 1954). Thus, myelinated axons of small diameter can transmit information as rapidly as much larger unmyelinated axons. Myelin therefore is an evolutionary innovation that allows the nervous system to increase in speed and complexity without a corresponding increase in size and energy requirements. Although some invertebrate species have myelinated axons, myelin is ubiquitous among the gnathostomes (jawed vertebrates), and this adaptation has surely been essential for the formation of the large, complex nervous systems that distinguish the vertebrates from other groups (Bunge, 1968; Hartline and Colman, 2007).

Disruption of the myelin sheath underlies many debilitating diseases including Multiple Sclerosis, Charcot Marie Tooth disease, and others (Berger et al., 2006; McQualter and Bernard, 2007). Specialized glial cells, oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS), wrap their membranes many times around a segment of an axon to form the myelin sheath (Bunge, 1968; Geren and Raskind, 1953; Peters, 1964). Along its length, each axon is ensheathed by multiple myelin segments, which are separated by unmyelinated gaps called nodes of Ranvier (Bunge, 1968; Stampfli, 1954; Tasaki, 1959). Oligodendrocytes interact with and elaborate myelin sheaths around many different axons; in contrast, Schwann cells myelinate only one segment of one axon (Bunge, 1968).

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Source: https://www.sciencedirect.com/topics/veterinary-science-and-veterinary-medicine/saltatory-conduction