Myelin and Action Potential
Propagation
Matthew N Rasband, State University of New York, Stony Brook, New York, USA
The high action potential conduction velocities achieved in some vertebrate axons are a
consequence of myelin, an insulating sheath made by glial cells, and clustered sodium ion
(Na 1 ) channels found at regularly spaced gaps in the myelin sheath.
Secondary article
Article Contents
. Introduction
. Wrapping of Glial Cells Around Axons
. Glial Cell Membranes as Electrical Insulators Around
Axons
. Interruption of the Glial Cell Wrapping at Nodes of
Ranvier
. Clustering of Sodium Channels at the Nodes of Ranvier
. Saltatory Conduction of Action Potentials from One
Node to Another
Introduction
Vertebrates have solved the problem of how to successfully
and rapidly transmit electrical signals over the immense
distances between the neuronal cell body and the axon
terminal, while minimizing space requirements, by the
development of both myelin and heterogeneous ion
channel localization. Myelin is a bimolecular leaflet of
glyco- and phospholipids, sandwiched between two
protein layers, that wraps an axon with numerous
concentric lamellae. These layers of membrane are extensions of satellite cells called glia. Myelin acts like an
insulating sheath, preventing the loss of current as the
action potential propagates along the axon. Sodium ion
(Na 1 ) channels, on the other hand, are found clustered at
regularly spaced gaps in the myelin sheath, called nodes of
Ranvier. These channels are responsible for the inward
currents that allow for the generation and propagation of
the action potential. Together, myelin and nodal Na 1
channels allow for conduction of electrical signals as fast as
120 m s 2 1, and discharge frequencies of hundreds of
impulses per second.
Wrapping of Glial Cells Around Axons
Only certain kinds of glial cells are responsible for making
myelin. Other, nonmyelinating glia, such as astrocytes and
microglia, perform neuroimmune, nutritive, ionic buffering, developmental and structural roles. In the peripheral
nervous system (PNS), myelin is made by Schwann cells. In
contrast, oligodendrocytes elaborate myelin in the central
nervous system (CNS).
Myelination in the peripheral nervous system
During early development of the PNS, Schwann cells
proliferate and associate both with those axons that are
destined to be myelinated and those that remain unmyelinated. Initially, all axons are enveloped by Schwann cells
until completely surrounded. The glia continue to divide,
and if an axon is to be myelinated, it is transferred to
daughter Schwann cells until only one glial cell wraps a
. Speed of Action Potential Propagation in Myelinated
and Nonmyelinated Axons
. Summary
single axon or fibre. In contrast, if the axon is to remain
unmyelinated, the Schwann cell still surrounds the axon,
but a single Schwann cell may enclose many fibres
(Figure 1a). Myelination commences after a one-to-one
association has been achieved between the myelinating
Schwann cells and axons, and as the latter reach a diameter
of about 1–2 mm. At this point, Schwann cells begin to
flatten, extend longitudinally along the length of the axon,
and wrap the fibre with concentric, spiralling layers of
cytoplasm (Figure 1a); the inner tongue of the Schwann cell
process is responsible for the wrapping. Compact myelin is
formed as the cytoplasm of each layer is gradually
extruded, until adjacent cytoplasmic faces of the membrane are directly apposed one to another. This process
continues until many layers of compact myelin are formed;
large fibres may have as many as 250–300 concentric wraps
of myelin, although small fibres have as few as five. The
longitudinal extension of Schwann cells also continues
during myelin formation and compaction until adjacent
myelinating Schwann cells are contacted. The narrow gap
between the cells defines a new node of Ranvier. Each
Schwann cell delineates a single internode, the segment
between nodes of Ranvier, and the length of internodes
may increase, both by the growth of the animal and by
competitive elimination of some Schwann cells, such that
the myelin sheath is continually modified during early
development. In adult animals, the internodal length varies
greatly, anywhere from 200 to 2000 mm, and is roughly 100
times the diameter of the fibre (Hildebrand and Johansson,
1991).
Myelination in the central nervous system
In contrast to Schwann cells, single oligodendrocytes in the
CNS extend numerous thin cytoplasmic processes, each of
which may contact a different axon, elongate, and then
wrap and ensheathe their associated axons (Figure 1a). The
most pronounced and obvious difference between central
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1
Myelin and Action Potential Propagation
PNS
CNS
Unmyelinated
Myelinated
(a)
PNS
Juxtaparanode
Paranode
Node
Kv1.1
Kv1.2
Kvβ2
Caspr
NaCh
Ankyrin-G
NrCAM
Neurofascin
CNS
(b)
Figure 1 Myelination (a) and morphology of the node of Ranvier (b) in the peripheral nervous system (PNS) and central nervous system (CNS). (a)
Cartoon of myelination shows that Schwann cells ensheathe unmyelinated axons in the PNS, but form myelin only after a one-to-one association has
occurred. Oligodendrocytes myelinate numerous axons in the CNS, and form shorter internodal lengths than in the PNS. The box at the bottom of the axon
contains a node of Ranvier and is shown at higher magnification in (b). (b) The myelin sheath is interrupted at regularly spaced nodes of Ranvier, where Na 1
channels are clustered in high density, and other molecules are discretely localized in the paranodal and juxtaparanodal subcellular zones. The top half of
the figure shows a node of Ranvier in the PNS; the lower shows a node in the CNS.
2
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
Myelin and Action Potential Propagation
and peripheral myelination is that a single oligodendrocyte
myelinates as many as 30–50 axons (Peters and Vaughn,
1970). Thus, myelinated segments from an oligodendrocyte can form distinct internodes that may be on the same
or different axons. One pathophysiological consequence of
this difference is that the loss or death of a single Schwann
cell only affects a single axon, whereas the death of an
oligodendrocyte is detrimental to conduction in numerous
axons. In contrast to the PNS, myelin compaction occurs
almost immediately after ensheathement. In general,
however, the processes of myelination in both the CNS
and PNS are very similar. This might also be expected, as
the role of myelin, both from functional and structural
perspectives, is identical.
Glial Cell Membranes as Electrical
Insulators Around Axons
Electrophysiologically, the myelin sheath serves a dual role
in support of action potential conduction and can be
thought of as a string of parallel resistances and
capacitances in series. First, the numerous lamellae of
protein and lipid create a high resistance barrier to the flow
of transverse current through internodal regions, and
electrically isolate the internodal axonal membrane.
Secondly, myelin decreases the internodal membrane
capacitance, as the latter is a function of the distance
between the two charge carriers (intracellular and extracellular spaces), thereby reducing the internodal capacitative current lost to membrane charging during action
potential propagation. Measurement of the internodal
resistance and capacitance of frog myelinated nerve fibres
has shown that they are 8000 and 0.0008 times that for
nodal resistance and capacitance, respectively (Aidley,
1991). As a result, the vast majority of the membrane
current (both ionic and capacitative) in myelinated axons is
seen only at nodes.
Interruption of the Glial Cell Wrapping
at Nodes of Ranvier
The myelin sheath is interrupted at regularly spaced, highly
specialized sites, called nodes of Ranvier, where a diverse
population of ion channels and other proteins are clustered
and localized to support rapid action potential conduction
(Figure 1b). The structure of the node of Ranvier differs only
slightly between CNS and PNS tissues. In particular, the
Schwann cell has several outermost layers of myelin which
do not terminate on the axonal membrane itself, but
instead form finger-like projections that extend across the
nodal gap and interdigitate with similar projections from
the opposite Schwann cell. In the CNS, all myelin lamellae
terminate in axoglial junctions adjacent to the node of
Ranvier, leaving the node itself exposed to the extracellular
space. The similarities and differences in nodal architecture
are shown in Figure 1b, where the top half of the axon is
shown myelinated by a Schwann cell, and the bottom half
by an oligodendrocyte. On average, the length of the nodal
gap in both CNS and PNS tissues is about 1 mm.
Immediately adjacent to the node itself is a region called
the paranode, where sequential layers of myelin terminate
in specialized, closely apposed axoglial junctions. These
junctions form a high resistance barrier to the flow of
longitudinal currents in the narrow ( 15-nm) internodal
periaxonal space between the axon and myelin, and may
also serve as a structural barrier to the lateral diffusion of
nodal and internodal molecules. Just beyond the innermost
axoglial junction is another specialized region called the
juxtaparanode, where, in large fibres, the axonal diameter
increases and flutes out (Figure 1b). This region extends for
approximately 5–20 mm into the internode, depending on
the diameter of the fibre. The majority of the axonal
membrane, beginning at the edge of the juxtaparanode, is
found beneath myelin, and is called the internode.
Molecular composition of the node of Ranvier
The node of Ranvier represents one of the most highly
specialized sites in the nervous system with respect to both
its molecular and structural organization. Ion channels
and adhesion molecules are organized in very discrete
locations that correspond precisely with the previously
described nodal, paranodal and juxtaparanodal structures.
In particular, Na 1 channels, ankyrin-G (ankyrin-3; the
cytoskeletal-binding protein thought to anchor Na 1
channels), and the ankyrin-G-binding cell adhesion
molecules neurofascin and NrCAM are all found localized
to the node (Davis et al., 1996). The cell adhesion molecule
Caspr (paranodin) has been found in, and restricted to, the
paranode and is an important component of paranodal
axoglial junctions, although the proteins with which Caspr
associate remain to be elucidated (Einheber et al., 1997). In
mammals, the juxtaparanode is the exclusive domain of
voltage-gated potassium ion (K 1 ) channels. Specifically,
the Shaker-like Kv1.1 and Kv1.2 subunits, and the
cytoplasmic Kvb2 subunit, form heteromultimeric K 1
channels at these sites (Rhodes et al., 1997).
Despite structural and cellular differences in myelination
between the CNS and PNS, the molecules found in nodal
zones are conserved in these two neuronal tissues. Figures 2a
and 2b show nodes of Ranvier from the PNS and CNS,
respectively. Na 1 channels can be seen focally clustered
between flanking zones of paranodal Caspr immunoreactivity. This entire nodal and paranodal apparatus is further
bounded by juxtaparanodal K 1 channels. A pronounced
feature that is readily apparent is the precise localization of
each of these molecules to specific ultrastructural domains.
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Myelin and Action Potential Propagation
the mechanisms whereby these high-density aggregates
arise. Most experiments have shown that nodes of Ranvier
have Na 1 channels in densities of several thousand
channels per square micrometre. As a result, the nodal
membrane is highly excitable and, upon depolarization, is
able to conduct a substantial amount of current.
How are these ion channels clustered in such highdensity aggregates and at regularly spaced sites, in some
cases more than a metre from the neuronal cell body? As
described above, during early development axons are
initially devoid of any overlying myelin but, importantly,
these same axons are able to support action potential
propagation at very slow velocities because they have a
uniformly distributed population of Na 1 channels (Waxman et al., 1989). Studies of myelination and ion channel
clustering have shown that these two processes are
intimately related. In particular, as myelination begins,
and as Schwann cells or oligodendrocytes ensheathe axons
and extend processes longitudinally along the length of
axons, Na 1 channel clusters form at the very edges of the
elongating cell. These channel aggregates migrate as the
glial cells continue to myelinate and grow. Finally, as
adjacent glial cells or processes come into close proximity,
the Na 1 channel clusters fuse, and form a new node of
Ranvier (Figure 2c). When myelination is pharmacologically, genetically or surgically disrupted, clusters do not
form. Instead, broad, diffuse Na 1 channel distributions
result. Thus, the formation of high-density aggregates at
nodes of Ranvier is dependent on myelinating glial cells
(Vabnick et al., 1996; Rasband et al., 1999). One other
significant consequence of this clustering process is
apparent in Figure 2c: Na 1 channels are markedly absent
from internodal regions. Consequently, the internodal
membrane lacks sufficient Na 1 channels to support action
potential conduction alone, and if myelin is experimentally
removed, conduction fails. The specific neuronal and glial
molecular mechanisms and events that occur to cause
clustering of node-specific molecules, and that target these
essential components of conduction to the axon and the
node of Ranvier, have not yet been determined and are an
active area of investigation.
Figure 2 The discrete molecular organization of ion channels in the rat
peripheral and central nervous systems. (a, b) Nodes of Ranvier in the
peripheral and central nervous systems, respectively, labelled for Na 1
channels (green), Caspr (red) and Kv1.2 K 1 channel a subunits (blue). (c)
Four myelinated axons from the peripheral nervous system, visualized
using Hoffman optics and immunofluorescence, two of which have Na 1
channels clustered in the nodal gap (green). Bars, 10 mm.
Clustering of Sodium Channels at the
Nodes of Ranvier
Nodal Na 1 channels have been the subject of many studies
to determine the density of channels, their function, and
4
Saltatory Conduction of Action
Potentials from One Node to Another
How do clustered, nodal Na 1 channels and myelin work
together to facilitate action potential conduction? As
described above, several factors inhibit the flow of
transmembrane currents in internodal regions. First, the
myelin sheath forms a high-resistance, low-capacitance,
barrier. Second, regions covered by myelin have a very low
density of Na 1 channels. And third, the paranodal
axoglial junctions and the small periaxonal space make
continuous conduction through the internode difficult
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Myelin and Action Potential Propagation
Speed of Action Potential Propagation
in Myelinated and Nonmyelinated
Axons
because of the very high external resistance through the
periaxonal space. Consequently, axoplasmic currents are
dissipated minimally in internodal regions. When a
depolarizing action potential is sufficient to excite a node
of Ranvier, the currents generated propagate down the low
resistance axoplasm until the next node is reached,
depolarizing it so that it too becomes excited, allowing
for inward Na+ currents that restore the amplitude of the
action potential and cause currents to continue to the next
node. This process continues as node after node is
depolarized and the action potential propagates down
the length of the axon (Figure 3). Since all transmembrane
currents occur at nodes of Ranvier, the site of active
excitation appears to jump or skip from node to node. This
type of action potential propagation is called ‘saltatory
conduction’, from the latin word saltare, to jump. Figure 3
shows that since there is very little internodal membrane
capacitance, the charge is found primarily at nodes of
Ranvier, and as positive charge travels along the axon,
nodes are activated one after the other, allowing for the
action potential to propagate, with the currents themselves
travelling through the axoplasm and the extracellular
space. Further, were the transmembrane currents to be
recorded at both nodal and internodal locations, currents
would be detected only at nodes, as shown at the bottom of
Experiments to measure the conduction velocities in
myelinated nerves have shown a wide range of values.
For example, in the mammalian PNS, myelinated sensory
fibres may vary in diameter from 1 to 20 mm, and
correspondingly have conduction velocities from 4.5 to
120 m s 2 1. Similarly, the action potential velocity in small
(1-mm) CNS myelinated axons are as high as 12 m s 2 1
(Rasband et al., 1999). In contrast, the very small
unmyelinated axons in the PNS that conduct action
potentials in response to nociceptive stimuli (pain), also
known as C fibres, have conduction velocities that range
from only 0.5 to 3.0 m s 2 1 (Paintal, 1978). Since signal
propagation depends on the ability of the action potential
to depolarize consecutive nodes, the conduction velocity
must be dependent on the distance between nodes. Further,
since the internodal length is directly proportional to the
diameter of the axon, the conduction velocity is also
proportional to the diameter. In contrast, both empirical
measurement and mathematical models of conduction in
unmyelinated axons have shown that the speed of action
potential propagation is proportional to the square root of
the axon diameter.
Although myelin’s most noticeable contribution is an
increase in the conduction velocity, there are several
Figure 3.
1
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3
4
5
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Direction of propagation
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Figure 3 Saltatory conduction in myelinated axons. Transmembrane currents appear to jump from node to node, as each depolarizing action potential
causes the next node to be excited (top). ( 1 , 2 ) show the relative charges at each point along the axon during action potential propagation. Further, were
transmembrane currents to be recorded at each of the sites indicated by the green arrows, they would be detected only at nodes of Ranvier (bottom).
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
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Myelin and Action Potential Propagation
additional important benefits of saltatory conduction.
First, since little charge is lost through internodal
transmembrane or capacitative currents, and the only site
of current loss is the node itself, the metabolic energy
required to recover excitability is reduced dramatically.
Second, the conduction velocity in myelinated axons is
roughly 10 times that of unmyelinated axons of equivalent
size. Therefore, since the conduction velocity in unmyelinated axons is proportional to the square root of the axonal
diameter, the number of myelinated fibres that can be used
in the same volume of space required by an unmyelinated
axon that conducts with an equivalent velocity increases by
100 times. As a result, myelination increases the speed of
action potential propagation, and decreases the space
required to achieve the increase in conduction velocity.
Finally, myelinated nerve fibres are able to conduct trains
of action potentials at higher frequencies than unmyelinated fibres, as the frequency depends largely on the
conduction velocity.
Summary
It is difficult to overstate the impact that myelination has
on action potential conduction and propagation. Myelin
functions not only to decrease the internodal transmembrane currents, but also to direct the incredibly precise and
regulated molecular organization of the membrane, such
that Na 1 channels and other important molecules are
clustered at, or near, regularly spaced nodes of Ranvier.
Consequently, the formation of myelin by glial cells and
the establishment of heterogeneous ion channel distributions allows efficient, faithful and rapid conduction
velocities in the vertebrate nervous system. However, since
myelin is so important, demyelinating diseases, like multiple sclerosis and Guillain–Barré syndrome, or injuries are
accompanied by failure of action potential conduction.
Efforts to find therapies and drugs to either repair
demyelinated axons, or restore conduction through
modulation of ion channels, have met with some limited
success and may promise a day when clinical intervention
can treat these debilitating diseases.
6
References
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Davis JQ, Lambert S and Bennett V (1996) Molecular composition of the
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nodal axon segments. Journal of Cell Biology 135: 1355–1367.
Einheber S, Zanazzi G, Ching W et al. (1997) The axonal membrane
protein Caspr, a homologue of neurexin IV, is a component of the
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Further Reading
Morell P (ed.) (1984) Myelin, 2nd edn. New York: Plenum Press.
Peters A, Palay SL and Webster HD (1976) The Fine Structure of the
Nervous System: The Neurons and Supporting Cells. Philadelphia: WB
Saunders.
Vabnick I and Shrager P (1998) Ion channel redistribution and function
during development of the myelinated axon. Journal of Neurobiology
37: 80–96.
Waxman SG and Ritchie JM (1993) Molecular dissection of the
myelinated axon. Annals of Neurology 33: 121–136.
Zagoren JC and Fedoroff S (eds) (1984) The Node of Ranvier. Orlando:
Academic Press.
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