Medical Physiology, 3rd Edition

Axonal Conduction

Axons are specialized for rapid, reliable, and efficient transmission of electrical signals

At first glance, the job of the axon seems mundane compared with the complex computational functions of synapses, dendrites, and somata. After all, the axon has the relatively simple job of carrying the computed signal—a sequence of action potentials—from one place in the brain to another without changing it significantly. Some axons are thin, unmyelinated, and slow; these properties are sufficient to achieve their functions. However, the axon can be exquisitely optimized, with myelin and nodes of Ranvier, for fast and reliable saltatory conduction of action potentials over very long distances (see p. 200). Consider the sensory endings in the skin of your foot, which must send their signals to your lumbar spinal cord 1 m away (see Fig. 10-11B). The axon of such a sensory cell transmits its message in just a few tens of milliseconds! As we see in our discussion of spinal reflexes on pages 392–395, axons of similar length carry signals in the opposite direction, from your spinal cord to the muscles within your feet, and they do it even faster than most of the sensory axons. Axons within the CNS can also be very long; examples include the corticospinal axons that originate in the cerebral cortex and terminate in the lumbar spinal cord. Alternatively, many central axons are quite short, only tens of micrometers in length, and they transmit their messages locally between neurons. The spinal interneuron between a sensory neuron and a motor neuron (see Fig. 10-11B) is an example. Some axons target their signal precisely, from one soma to only a few other cells, whereas others may branch profusely to target thousands of postsynaptic cells.

Different parts of the brain have different signaling needs, and their axons are adapted to the local requirements. Nevertheless, the primary function of all axons is to carry electrical signals, in the form of action potentials, from one place to other places and to do so rapidly, efficiently, and reliably. Without myelinated axons, the large, complex brains necessary to control warm, fast mammalian bodies could not exist. For unmyelinated axons to conduct action potentials sufficiently fast for many purposes, their diameters would have to be so large that the axons alone would take up far too much space and use impossibly large amounts of energy.

Action potentials are usually initiated at the initial segment

The soma, axon hillock, and initial segment of the axon together serve as a kind of focal point in most neurons. The many graded synaptic potentials carried by numerous dendrites converge at the soma and generate one electrical signal. During the 1950s, Sir John Eccles image N12-2 and colleagues used glass microelectrodes to probe the details of this process in spinal motor neurons. Because it appeared that the threshold for action potentials in the initial segment was only ~10 mV above the resting potential, whereas the threshold in the soma was closer to 30 mV above resting potential, they concluded that the neuron's action potentials would be first triggered at the initial segment. Direct recordings from various parts of neurons now indicate that spikes begin at the initial segment, at least for many types of vertebrate neurons. EPSPs evoked in the dendrites propagate down to and through the soma and trigger an action potential in a myelin-free zone of axon ~15 to 50 µm from the soma (Fig. 12-5A). The action potential then propagates in two directions: forward—orthrodromic conduction—into the axon, with no loss of amplitude, and backward—antidromic conduction—into the soma and dendrites, with strong attenuation, as we saw above in Figure 12-3. Orthodromic propagation carries the signal to the next set of neurons. The function of antidromic propagation is not completely understood. It is very likely that backwardly propagating spikes trigger biochemical changes in the neuron's dendrites and synapses and they may have a role in plasticity of synapses and intrinsic membrane properties.


FIGURE 12-5 Simultaneous recording of action potentials from different parts of a neuron. A, In this hypothetical experiment, an excitatory synapse on a dendrite is stimulated and the response near that dendrite is recorded in the soma and at the initial segment. The EPSP attenuates in the soma and the initial segment, but the EPSP is large enough to trigger an action potential at the initial segment. B, The threshold is high (–35 mV) in regions of the neuron that have few Na+ channels but starts to fall rather steeply in the hillock and initial segment. Typically, a stimulus of sufficient strength triggers an action potential at the initial segment. C, The density of Na+ channels is high only at the initial segment and at each node of Ranvier.


Sir John Carew Eccles

For more information about Sir John Carew Eccles and the work that led to his Nobel Prize, visit (accessed October 2014).

The axon achieves a uniquely low threshold in its initial segment (see Fig. 12-5B) by two main mechanisms. First, the initial segment has a remarkably high density of voltage-gated Na+ channels (see Fig. 12-5C). The Na+ channel density in the axon initial segment is estimated to be 3-fold to 40-fold higher than in the membrane of the soma and dendrites, depending on neuron type and experimental methodology. The scaffolding protein ankyrin-G is a molecular marker for the initial segment and seems to be critical for organizing its unique distribution of ion channels. Second, initial segments often include Na+ channel types (see Table 7-1) such as Nav1.6 that activate at relatively negative voltages compared to channels such as Nav1.2 that are common in the soma and dendrites. The combination of large numbers of Na+ channels and their opening at relatively negative voltage allows the initial segment to reach action potential threshold before other sites on the dendrites and soma.

Conduction velocity of a myelinated axon increases linearly with diameter

The larger the diameter of an axon, the faster its conduction velocity, other things remaining equal. However, conduction velocity is usually much faster in myelinated axons than it is in unmyelinated axons (see p. 200). Thus, a myelinated axon 10 µm in diameter conducts impulses at about the same velocity as an unmyelinated axon ~500 µm in diameter. Myelination confers not only substantial speed advantages but also advantages in efficiency. Almost 2500 of the 10-µm myelinated axons can pack into the volume occupied by one 500-µm axon!

Unmyelinated axons still have a role in vertebrates. At diameters below ~1 µm, unmyelinated axons in the peripheral nervous system (PNS) conduct more rapidly than myelinated ones do. In a testament to evolutionary frugality, the thinnest axons of the peripheral sensory nerves, called C fibers, are ~1 µm wide or less, and all are unmyelinated. Axons larger than ~1 µm in diameter are all myelinated (Table 12-1). Every axon has its biological price: the largest axons obviously take up the most room and are the most expensive to synthesize and to maintain metabolically. The largest, swiftest axons are therefore used sparingly. They are used only to carry sensory information about the most rapidly changing stimuli over the longest distances (e.g., stretch receptors in muscle, mechanoreceptors in tendons and skin), or they are used to control finely coordinated contractions of muscles. The thinnest, slowest C fibers in the periphery are mainly sensory axons related to chronic pain and temperature sensation, for which the speed of the message is not as critical.

TABLE 12-1

Classes of Peripheral Sensory and Motor Axons, by Size and Conduction Velocity







Sensory afferents from proprioceptors of skeletal muscle
Motor neurons to skeletal muscle

Sensory afferents from mechanoreceptors of skin

Motor fibers to intrafusal fibers of muscle spindles

Sensory afferents from pain and temperature receptors

Preganglionic neurons of the ANS

Sensory afferents from pain, temperature and itch receptors

Diameter (µm)







Conduction velocity of action potential (m/s)







Alternative classification of sensory axons from muscle and tendon

Ia (sensory from muscle spindle fibers)
Ib (sensory from Golgi tendon organs)






*This A–C classification was introduced by Joseph Erlanger and Herbert Gasser, who shared the 1944 Nobel Prize in Medicine or Physiology for describing the relationship among axon diameter, conduction velocity, and function in a complex peripheral nerve. image N12-4


Joseph Erlanger and Herbert Gasser

For more information about Joseph Erlanger and Herbert Gasser and the work that led to their Nobel Prize, visit (assessed October 2014).

This I–IV classification was introduced by other investigators. It applies only to sensory axons and only to those from muscle and tendon.

ANS, autonomic nervous system.

Modified from Bear MF, Connors BW, Paradiso MP: Neuroscience: Exploring the Brain, 2nd ed. Baltimore, Lippincott Williams & Wilkins, 2001.

The relationship between form and function for axons in the CNS is less obvious than it is for those in the PNS, in part because it is more difficult to identify each axon's function. Interestingly, in the brain and spinal cord, the critical diameter for the myelination transition may be smaller than in the periphery. Many central myelinated axons are as thin as 0.2 µm. At the other extreme, very few myelinated central axons are >4 µm in diameter.

The myelinated axon membrane has a variety of ion channels that may contribute to its normal and pathological function. Of primary importance is the voltage-gated Na+ channel, which provides the rapidly activating and inactivating inward current that yields the action potential. Nine isoforms of the α subunit of the voltage-gated Na+ channel exist (see Table 7-1). In normal central axons, it is specifically Nav1.6 channels that populate mature nodes of Ranvier at a density of 1000 to 2000 channels per square micrometer (see Fig. 12-5). The same axonal membrane in the internodal regions, under the myelin, has <25 channels per square micrometer (versus between 2 and 200 channels per square micrometer in unmyelinated axons). The dramatically different distribution of channels between nodal and internodal membrane has important implications for conduction along pathologically demyelinated axons (see below). K+ channels are relatively less important in myelinated axons than they are in most other excitable membranes. Very few of these channels are present in the nodal membrane, and fast K+ currents contribute little to repolarization of the action potential in mature myelinated axons. This diminished role for K+ channels may be a cost-cutting adaptation because the absence of K+ currents decreases the metabolic expense of a single action potential by ~40%. However, some K+ channels are located in the axonal membrane under the myelin, particularly in the paranodal region. The function of these K+ channels is unclear; they may set the resting Vm of the internodes and help stabilize the firing properties of the axon.

Demyelinated axons conduct action potentials slowly, unreliably, or not at all

Numerous clinical disorders selectively damage or destroy myelin sheaths and leave the axonal membranes intact but bare. These demyelinating diseases may affect either peripheral or central axons and can lead to severely impaired conduction (Fig. 12-6). The most common demyelinating disease of the CNS is multiple sclerosis (Box 12-1), a progressive disorder characterized by distributed zones of demyelination in the brain and spinal cord. The specific clinical signs of these disorders vary and depend on the particular sets of axons affected.


FIGURE 12-6 Demyelination in the CNS. A cross section of a spinal root from a dystrophic mouse shows amyelinated bundles of axons (thin borders) surrounded by myelinated fibers (thick borders). V, vein. (From Rosenbluth J: In Waxman SG, Kocsis JD, Stys PK [eds]: The Axon: Structure, Function, and Pathophysiology. New York, Oxford University Press, 1995.)

Box 12-1

Demyelinating Diseases

Multiple sclerosis (MS), the most common demyelinating disease of the CNS, affects >350,000 Americans. MS is an autoimmune disease directed against the myelin or oligodendrocytes (see p. 292) and is thus a purely CNS disease. The trigger is unclear. Some have proposed a viral antigen (including canine distemper virus), but many other theories abound, none of which has been clearly proven. The viral antigen theory is based at least in part on classic studies that concluded that MS has a greater incidence in temperate regions than in the tropics and that one's risk depends on where one spent one's childhood, not adulthood. No good evidence has been presented for a viral etiology yet. MS is twice as common in women as in men. Susceptibility to MS has also been linked to a number of genetic alleles of the human leukocyte antigen (HLA) system.

The signs and symptoms of MS are protean, but common features include the following:

1. An optic neuritis may cause decreased visual acuity.

2. Lesions of axons important for controlling eye movements may cause double vision.

3. The Lhermitte sign is an electrical sensation that shoots down the back and into the legs when the neck is flexed.

Magnetic resonance imaging can demonstrate the lesions in MS. Evoked potential studies, which measure nerve fiber conduction in various sensory pathways, yield abnormal results in almost all established cases and in about two thirds of suspected cases of MS.

MS is defined clinically as a disease that involves demyelination of the CNS with episodes separated in both time and space—at least two episodes of demyelination involving at least two separated regions of the CNS. Remissions and relapses are very common with MS. An exacerbation is due to the occurrence of active inflammation of a white matter tract in the CNS. A remission occurs when the inflammation subsides and the axons that have been demyelinated recover some of their function and are able to conduct action potentials through the area of myelin damage. However, the pathologically demyelinated fibers are not normal. Among the molecular changes that occur may be replacement of Nav1.6 channels by Nav1.2 channels in demyelinated axons. Conduction is often barely adequate under normal circumstances and may become inadequate under stressful situations, such as illness, emotional stress, and exhaustion. Under these circumstances, symptoms will reappear.

The reasons for remissions and exacerbations are not entirely clear. Conduction in the pathologically demyelinated fibers that is just barely adequate under normal circumstances may become inadequate under certain stressful situations, such as illness, emotional stress, and exhaustion; only then will symptoms become evident. A change in temperature is a classic example of circumstances changing conduction. Conduction through demyelinated axons is actually “safer” at low temperatures that slow the gating kinetics of Na+ channels, lengthen the action potentials, and slow conduction velocity. The augmented currents of the broader spike make it more likely that the threshold for continued conduction will be reached. image N12-3 When the body temperature of a patient with MS is elevated, for example, by fever or immersion in a hot bath, conduction is compromised and neurological deficits may appear.


Temperature Dependence of Axonal Conduction

Contributed by Barry Connors

For a myelinated axon, decrease of just 2°C increases the duration of an action potential by ~20%. As shown in eFigure 12-2, a temperature decrease of 7°C has an even greater effect on a myelinated axon. In the case of a demyelinated axon, a temperature decrease of 7°C can permit an action potential where one was previously not possible.


EFIGURE 12-2 Temperature dependence of axonal conduction. (Data from Sears TA, Bostock H: Conduction failure in demyelination: Is it inevitable? Adv Neurol 31:357–375, 1981.)

Certain drugs can also prolong the duration of action potentials and facilitate conduction through demyelinated axons. Demyelination may expose the voltage-gated K+ channels, which are normally hidden under the myelin. Activation of outwardly rectifying K+ channels can further impair spike production in demyelinated axons. However, the K+ channels also become accessible to pharmacological agents, such as the class of K+ channel blockers called aminopyridines (see pp. 195–196). Blocking these K+ channels can prolong the spike and facilitate its propagation through demyelinated regions. A slow-release formulation of 4-aminopyridine is now available for the symptomatic treatment of MS.

At present, standard treatment of MS exacerbations includes immunosuppressive agents. The most common is interferon-β, which has antiviral, antiproliferative, and immune-modulating activity. Many newer drugs are under investigation to help prevent the autoimmune attack, to reduce the damage during an attack, or to improve function in already demyelinated regions.

The most common demyelinating disease of the PNS is Landry-Guillain-Barré syndrome. After a respiratory or other viral infection, an ascending neurological syndrome develops that is characterized by the onset of weakness, leading to paralysis of the legs and subsequent involvement of the hands and arms. In severe cases, the paralysis involves the cranial nerves, and patients may lose the ability to swallow or even to breathe, which requires mechanical ventilation for a time. This initial stage of Landry-Guillain-Barré syndrome reaches a plateau in several weeks and then gradually resolves. Most patients recover completely as long as the physician recognizes the syndrome and initiates supportive treatment. Untreated, this syndrome is often fatal.

Landry-Guillain-Barré syndrome is caused by autoimmunity to the myelin sheath produced by Schwann cells in the PNS (see p. 292). These patients generally recover fully because the PNS has the ability to remyelinate itself. Axons of the CNS do not remyelinate to any significant extent, which explains why complete recovery in patients with MS is not common.

In a normal, myelinated axon, the action currents generated at a node can effectively charge the adjacent node and bring it to threshold within ~20 µsec (Fig. 12-7A), because myelin serves to increase the resistance and to reduce the capacitance of the pathways between the axoplasm and the extracellular fluid (see pp. 199–201). The inward membrane current flowing across each node is actually 5-fold to 7-fold higher than necessary to initiate an action potential at the adjacent node. Removal of the insulating myelin, however, means that the same nodal action current is distributed across a much longer, leakier, higher-capacitance stretch of axonal membrane (see Fig. 12-7B). Several consequences are possible. Compared with normal conduction, conduction in a demyelinated axon may continue, but at a lower velocity, if the demyelination is not too severe (see Fig. 12-7B, record 1). In experimental studies, the internodal conduction time through demyelinated fibers can be as slow as 500 µs, 25 times longer than normal. The ability of axons to transmit high-frequency trains of impulses may also be impaired (see Fig. 12-7B, record 2). Extensive demyelination of an axon causes total blockade of conduction (see Fig. 12-7B, record 3). Clinical studies indicate that the blockade of action potentials is more closely related to symptoms than is the simple slowing of conduction. Demyelinated axons can also become the source of spontaneous, ectopically generated action potentials because of changes in their intrinsic excitability (see Fig. 12-7B, record 4) or mechanosensitivity (see Fig. 12-7B, record 5). Moreover, the signal from one demyelinated axon can excite an adjacent demyelinated axon and induce crosstalk (see Fig. 12-7C), which may cause action potentials to be conducted in both directions in the adjacent axon.


FIGURE 12-7 Demyelination. A, Four action potentials at the leftmost node of Ranvier are conducted—unchanged in amplitude and frequency—to the nodes that are farther to the right. B, Action potentials propagate from a normally myelinated region into a demyelinated area. The axial action current that was generated at the last healthy node is distributed across a long region of bare or partially myelinated axonal membrane, with its decreased resistivity and increased capacitance. Thus, the current density at the two affected nodes is greatly reduced. This panel shows five consequences of demyelination: (1) decreased velocity, which is manifested as longer delays for the arrival of the train of spikes; (2) frequency-related block, which does not pass high-frequency trains—as a result, some of the spikes are missing distally; (3) total blockade; (4) ectopic impulse generation—even though there is no input in the proximal portion of the axon, action potentials arise spontaneously beyond the lesion; and (5) increased mechanosensitivity—ectopic action potentials arise from mechanical stimulation. C, If the demyelination affects two adjacent axons, action potentials in one (the top axon in this case) cause action potentials to propagate in both directions in the adjacent axon.