Ganong’s Review of Medical Physiology, 24th Edition
CHAPTER 4 Excitable Tissue: Nerve
After studying this chapter, you should be able to:
Name the various types of glia and their functions.
Name the parts of a neuron and their functions.
Describe the chemical nature of myelin, and summarize the differences in the ways in which unmyelinated and myelinated neurons conduct impulses.
Describe orthograde and retrograde axonal transport.
Describe the changes in ionic channels that underlie the action potential.
List the various nerve fiber types found in the mammalian nervous system.
Describe the function of neurotrophins.
The human central nervous system (CNS) contains about 1011 (100 billion) neurons. It also contains 10–50 times this number of glial cells. The CNS is a complex organ; it has been calculated that 40% of the human genes participate, at least to a degree, in its formation. The neurons, the basic building blocks of the nervous system, have evolved from primitive neuroeffector cells that respond to various stimuli by contracting. In more complex animals, contraction has become the specialized function of muscle cells, whereas integration and transmission of nerve impulses have become the specialized functions of neurons. Neurons and glial cells along with brain capillaries form a functional unit that is required for normal brain function, including synaptic activity, extracellular fluid homeostasis, energy metabolism, and neural protection. Disturbances in the interaction of these elements are the pathophysiological basis for many neurological disorders (eg, cerebral ischemia, seizures, neurodegenerative diseases, and cerebral edema). This chapter describes the cellular components of the CNS and the excitability of neurons, which involves the genesis of electrical signals that enable neurons to integrate and transmit impulses (eg, action potentials, receptor potentials, and synaptic potentials).
CELLULAR ELEMENTS IN THE CNS
For many years following their discovery, glial cells (or glia) were viewed as CNS connective tissue. In fact, the word glia is Greek for glue. However, today theses cells are recognized for their role in communication within the CNS in partnership with neurons. Unlike neurons, glial cells continue to undergo cell division in adulthood and their ability to proliferate is particularly noticeable after brain injury (eg, stroke).
There are two major types of glial cells in the vertebrate nervous system: microglia and macroglia. Microglia are scavenger cells that resemble tissue macrophages and remove debris resulting from injury, infection, and disease (eg, multiple sclerosis, AIDS-related dementia, Parkinson disease, and Alzheimer disease). Microglia arise from macrophages outside of the nervous system and are physiologically and embryologically unrelated to other neural cell types.
There are three types of macroglia: oligodendrocytes, Schwann cells, and astrocytes (Figure 4–1). Oligodendrocytes and Schwann cells are involved in myelin formation around axons in the CNS and peripheral nervous system, respectively. Astrocytes, which are found throughout the brain, are of two subtypes. Fibrous astrocytes, which contain many intermediate filaments, are found primarily in white matter. Protoplasmic astrocytes are found in gray matter and have a granular cytoplasm. Both types send processes to blood vessels, where they induce capillaries to form the tight junctions making up the blood–brain barrier. They also send processes that envelop synapses and the surface of nerve cells. Protoplasmic astrocytes have a membrane potential that varies with the external K+ concentration but do not generate propagated potentials. They produce substances that are tropic to neurons, and they help maintain the appropriate concentration of ions and neurotransmitters by taking up K+ and the neurotransmitters glutamate and γ-aminobutyrate (GABA).
FIGURE 4–1 The principal types of macroglia in the nervous system. A) Oligodendrocytes are small with relatively few processes. Those in the white matter provide myelin, and those in the gray matter support neurons. B) Schwann cells provide myelin to the peripheral nervous system. Each cell forms a segment of myelin sheath about 1 mm long; the sheath assumes its form as the inner tongue of the Schwann cell turns around the axon several times, wrapping in concentric layers. Intervals between segments of myelin are the nodes of Ranvier. C) Astrocytes are the most common glia in the CNS and are characterized by their starlike shape. They contact both capillaries and neurons and are thought to have a nutritive function. They are also involved in forming the blood–brain barrier. (From Kandel ER, Schwartz JH, Jessell TM (editors): Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)
Neurons in the mammalian CNS come in many different shapes and sizes. Most have the same parts as the typical spinal motor neuron illustrated in Figure 4–2. The cell body (soma) contains the nucleus and is the metabolic center of the neuron. Neurons have several processes called dendrites that extend outward from the cell body and arborize extensively. Particularly in the cerebral and cerebellar cortex, the dendrites have small knobby projections called dendritic spines. A typical neuron also has a long fibrous axon that originates from a somewhat thickened area of the cell body, the axon hillock. The first portion of the axon is called the initial segment. The axon divides into presynaptic terminals, each ending in a number of synaptic knobs which are also called terminal buttons or boutons. They contain granules or vesicles in which the synaptic transmitters secreted by the nerves are stored. Based on the number of processes that emanate from their cell body, neurons can be classified as unipolar, bipolar, and multipolar (Figure 4–3).
FIGURE 4–2 Motor neuron with a myelinated axon. A motor neuron is comprised of a cell body (soma) with a nucleus, several processes called dendrites, and a long fibrous axon that originates from the axon hillock. The first portion of the axon is called the initial segment. A myelin sheath forms from Schwann cells and surrounds the axon except at its ending and at the nodes of Ranvier. Terminal buttons (boutons) are located at the terminal endings.
FIGURE 4–3 Some of the types of neurons in the mammalian nervous system. A) Unipolar neurons have one process, with different segments serving as receptive surfaces and releasing terminals. B) Bipolar neurons have two specialized processes: a dendrite that carries information to the cell and an axon that transmits information from the cell. C) Some sensory neurons are in a subclass of bipolar cells called pseudo-unipolar cells. As the cell develops, a single process splits into two, both of which function as axons—one going to skin or muscle and another to the spinal cord. D) Multipolar cells have one axon and many dendrites. Examples include motor neurons, hippocampal pyramidal cells with dendrites in the apex and base, and cerebellar Purkinje cells with an extensive dendritic tree in a single plane. (From Kandel ER, Schwartz JH, Jessell TM (editors): Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)
The conventional terminology used for the parts of a neuron works well enough for spinal motor neurons and interneurons, but there are problems in terms of “dendrites” and “axons” when it is applied to other types of neurons found in the nervous system. From a functional point of view, neurons generally have four important zones: (1) a receptor, or dendritic zone, where multiple local potential changes generated by synaptic connections are integrated; (2) a site where propagated action potentials are generated (the initial segment in spinal motor neurons, the initial node of Ranvier in cutaneous sensory neurons); (3) an axonal process that transmits propagated impulses to the nerve endings; and (4) the nerve endings, where action potentials cause the release of synaptic transmitters. The cell body is often located at the dendritic zone end of the axon, but it can be within the axon (eg, auditory neurons) or attached to the side of the axon (eg, cutaneous neurons). Its location makes no difference as far as the receptor function of the dendritic zone and the transmission function of the axon are concerned.
The axons of many neurons are myelinated, that is, they acquire a sheath of myelin, a protein–lipid complex that is wrapped around the axon (Figure 4–1B). In the peripheral nervous system, myelin forms when a Schwann cell wraps its membrane around an axon up to 100 times. The myelin is then compacted when the extracellular portions of a membrane protein called protein zero (P0) lock to the extracellular portions of P0 in the apposing membrane. Various mutations in the gene for P0 cause peripheral neuropathies; 29 different mutations have been described that cause symptoms ranging from mild to severe. The myelin sheath envelops the axon except at its ending and at the nodes of Ranvier, periodic 1-μm constrictions that are about 1 mm apart (Figure 4–2). The insulating function of myelin is discussed later in this chapter. Not all neurons are myelinated; some are unmyelinated, that is, simply surrounded by Schwann cells without the wrapping of the Schwann cell membrane that produces myelin around the axon.
In the CNS of mammals, most neurons are myelinated, but the cells that form the myelin are oligodendrocytes rather than Schwann cells (Figure 4–1). Unlike the Schwann cell, which forms the myelin between two nodes of Ranvier on a single neuron, oligodendrocytes emit multiple processes that form myelin on many neighboring axons. In multiple sclerosis, a crippling autoimmune disease, patchy destruction of myelin occurs in the CNS (see Clinical Box 4–1). The loss of myelin is associated with delayed or blocked conduction in the demyelinated axons.
CLINICAL BOX 4–1
Normal conduction of action potentials relies on the insulating properties of myelin. Thus, defects in myelin can have major adverse neurological consequences. One example is multiple sclerosis (MS), an autoimmune disease that affects over 3 million people worldwide, usually striking between the ages of 20 and 50 and affecting women about twice as often as men. The cause of MS appears to include both genetic and environmental factors. It is most common among Caucasians living in countries with temperate climates including Europe, southern Canada, northern United States, and southeastern Australia. Environmental triggers include early exposure to viruses such as Epstein-Barr virus and those that cause measles, herpes, chicken pox, or influenza. In MS, antibodies and white blood cells in the immune system attack myelin, causing inflammation and injury to the sheath and eventually the nerves that it surrounds. Loss of myelin leads to leakage of K+ through voltage-gated channels, hyperpolarization, and failure to conduct action potentials. Initial presentation commonly includes reports of paraparesis (weakness in lower extremities) that may be accompanied by mild spasticity and hyperreflexia; paresthesia; numbness; urinary incontinence; and heat intolerance. Clinical assessment often reports optic neuritis, characterized by blurred vision, a change in color perception, visual field defect (central scotoma), and pain with eye movements; dysarthria; and dysphagia. Symptoms are often exacerbated by increased body temperature or ambient temperature. Progression of the disease is quite variable. In the most common form called relapsing-remitting MS, transient episodes appear suddenly, last a few weeks or months, and then gradually disappear. Subsequent episodes can appear years later, and eventually full recovery does not occur. Many of these individuals later develop a steadily worsening course with only minor periods of remission (secondary-progressive MS). Others have a progressive form of the disease in which there are no periods of remission (primary-progressive MS). Diagnosing MS is very difficult and generally is delayed until multiple episodes occur with deficits separated in time and space. Nerve conduction tests can detect slowed conduction in motor and sensory pathways. Cerebral spinal fluid analysis can detect the presence of oligoclonal bands indicative of an abnormal immune reaction against myelin. The most definitive assessment is magnetic resonance imaging (MRI) to visualize multiple scarred (sclerotic) areas or plaques in the brain. These plaques often appear in the periventricular regions of the cerebral hemispheres.
Although there is no cure for MS, corticosteroids (eg, prednisone) are the most common treatment used to reduce the inflammation that is accentuated during a relapse. Some drug treatments are designed to modify the course of the disease. For example, daily injections of β-interferons suppress the immune response to reduce the severity and slow the progression of the disease. Glatiramer acetate may block the immune system’s attack on the myelin. Natalizumab interferes with the ability of potentially damaging immune cells to move from the bloodstream to the CNS. A recent clinical trial using B cell–depleting therapy with rituximab, an anti-CD20 monoclonal antibody, showed that the progression of the disease was slowed in patients under the age of 51 who were diagnosed with the primary-progressive form of MS. Another recent clinical trial has shown that oral administration of fingolimodslowed the progression of the relapsing-remitting form of MS. This immunosuppressive drug acts by sequestering lymphocytes in the lymph nodes, thereby limiting their access to the CNS.
Neurons are secretory cells, but they differ from other secretory cells in that the secretory zone is generally at the end of the axon, far removed from the cell body. The apparatus for protein synthesis is located for the most part in the cell body, with transport of proteins and polypeptides to the axonal ending by axoplasmic flow. Thus, the cell body maintains the functional and anatomic integrity of the axon; if the axon is cut, the part distal to the cut degenerates (wallerian degeneration).
Orthograde transport occurs along microtubules that run along the length of the axon and requires two molecular motors, dynein and kinesin (Figure 4–4). Orthograde transport moves from the cell body toward the axon terminals. It has both fast and slow components; fast axonal transport occurs at about 400 mm/day, and slow axonal transport occurs at 0.5 to 10 mm/day. Retrograde transport, which is in the opposite direction (from the nerve ending to the cell body), occurs along microtubules at about 200 mm/day. Synaptic vesicles recycle in the membrane, but some used vesicles are carried back to the cell body and deposited in lysosomes. Some materials taken up at the ending by endocytosis, including nerve growth factor (NGF) and some viruses, are also transported back to the cell body. A potentially important exception to these principles seems to occur in some dendrites. In them, single strands of mRNA transported from the cell body make contact with appropriate ribosomes, and protein synthesis appears to create local protein domains.
FIGURE 4–4 Axonal transport along microtubules by dynein and kinesin. Fast (400 mm/day) and slow (0.5–10 mm/day) axonal orthograde transport occurs along microtubules that run along the length of the axon from the cell body to the terminal. Retrograde transport (200 mm/day) occurs from the terminal to the cell body. (From Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology. McGraw-Hill, 2008.)
EXCITATION & CONDUCTION
A hallmark of nerve cells is their excitable membrane. Nerve cells respond to electrical, chemical, or mechanical stimuli. Two types of physicochemical disturbances are produced: local, nonpropagated potentials called, depending on their location, synaptic, generator, or electrotonic potentials; and propagated potentials, the action potentials (or nerve impulses). Action potentials are the primary electrical responses of neurons and other excitable tissues, and they are the main form of communication within the nervous system. They are due to changes in the conduction of ions across the cell membrane. The electrical events in neurons are rapid, being measured in milliseconds (ms); and the potential changes are small, being measured in millivolts (mV).
The impulse is normally transmitted (conducted) along the axon to its termination. Nerves are not “telephone wires” that transmit impulses passively; conduction of nerve impulses, although rapid, is much slower than that of electricity. Nerve tissue is in fact a relatively poor passive conductor, and it would take a potential of many volts to produce a signal of a fraction of a volt at the other end of a meter-long axon in the absence of active processes in the nerve. Instead, conduction is an active, self-propagating process, and the impulse moves along the nerve at a constant amplitude and velocity. The process is often compared to what happens when a match is applied to one end of a trail of gunpowder; by igniting the powder particles immediately in front of it, the flame moves steadily down the trail to its end as it is extinguished in its wake.
RESTING MEMBRANE POTENTIAL
When two electrodes are connected through a suitable amplifier and placed on the surface of a single axon, no potential difference is observed. However, if one electrode is inserted into the interior of the cell, a constant potential difference is observed, with the inside negative relative to the outside of the cell at rest. A membrane potential results from separation of positive and negative charges across the cell membrane (Figure 4–5).
FIGURE 4–5 A membrane potential results from separation of positive and negative charges across the cell membrane. The excess of positive charges (red circles) outside the cell and negative charges (blue circles) inside the cell at rest represents a small fraction of the total number of ions present. (From Kandel ER, Schwartz JH, Jessell TM (editors): Principles of Neural Science, 4th ed. McGraw-Hill, 2000.).
In order for a potential difference to be present across a membrane lipid bilayer, two conditions must be met. First, there must be an unequal distribution of ions of one or more species across the membrane (ie, a concentration gradient). Second, the membrane must be permeable to one or more of these ion species. The permeability is provided by the existence of channels or pores in the bilayer; these channels are usually permeable to a single species of ions. The resting membrane potential represents an equilibrium situation at which the driving force for the membrane-permeant ions down their concentration gradients across the membrane is equal and opposite to the driving force for these ions down their electrical gradients.
In neurons, the concentration of K+ is much higher inside than outside the cell, while the reverse is the case for Na+. This concentration difference is established by Na, K ATPase. The outward K+ concentration gradient results in passive movement of K+ out of the cell when K+-selective channels are open. Similarly, the inward Na+ concentration gradient results in passive movement of Na+ into the cell when Na+-selective channels are open.
In neurons, the resting membrane potential is usually about –70 mV, which is close to the equilibrium potential for K+ (step 1 in Figure 4–6). Because there are more open K+ channels than Na+ channels at rest, the membrane permeability to K+ is greater. Consequently, the intracellular and extracellular K+ concentrations are the prime determinants of the resting membrane potential, which is therefore close to the equilibrium potential for K+. Steady ion leaks cannot continue forever without eventually dissipating the ion gradients. This is prevented by the Na, K ATPase, which actively moves Na+ and K+ against their electrochemical gradients.
FIGURE 4–6 Changes in membrane potential and relative membrane permeability to Na+ and K+ during an action potential. Steps 1 through 7 are detailed in the text. These changes in threshold for activation (excitability) are correlated with the phases of the action potential. (Modified from Silverthorn DU: Human Physiology: An Integrated Approach, 5th ed. Pearson, 2010.)
IONIC FLUXES DURING THE ACTION POTENTIAL
The cell membranes of nerves, like those of other cells, contain many different types of ion channels. Some of these are voltage-gated and others are ligand-gated. It is the behavior of these channels, and particularly Na+ and K+channels, which explains the electrical events in neurons.
The changes in membrane conductance of Na+ and K+ that occur during the action potentials are shown by steps 1 through 7 in Figure 4–6. The conductance of an ion is the reciprocal of its electrical resistance in the membrane and is a measure of the membrane permeability to that ion. In response to a depolarizing stimulus, some of the voltage-gated Na+ channels open and Na+ enters the cell and the membrane is brought to its threshold potential (step 2) and the voltage-gated Na+ channels overwhelm the K+ and other channels. The entry of Na+ causes the opening of more voltage-gated Na+ channels and further depolarization, setting up a positive feedback loop. The rapid upstroke in the membrane potential ensues (step 3). The membrane potential moves toward the equilibrium potential for Na+ (+60 mV) but does not reach it during the action potential (step 4), primarily because the increase in Na+conductance is short-lived. The Na+ channels rapidly enter a closed state called the inactivated state and remain in this state for a few milliseconds before returning to the resting state, when they again can be activated. In addition, the direction of the electrical gradient for Na+ is reversed during the overshoot because the membrane potential is reversed, and this limits Na+ influx; also the voltage-gated K+ channels open. These factors contribute to repolarization. The opening of voltage-gated K+ channels is slower and more prolonged than the opening of the Na+ channels, and consequently, much of the increase in K+ conductance comes after the increase in Na+ conductance (step 5). The net movement of positive charge out of the cell due to K+ efflux at this time helps complete the process of repolarization. The slow return of the K+ channels to the closed state also explains the after-hyperpolarization(step 6), followed by a return to the resting membrane potential (step 7). Thus, voltage-gated K+ channels bring the action potential to an end and cause closure of their gates through a negative feedback process. Figure 4–7 shows the sequential feedback control in voltage-gated K+ and Na+ channels during the action potential.
FIGURE 4–7 Feedback control in voltage-gated ion channels in the membrane. A) Na+ channels exert positive feedback. B) K+ channels exert negative feedback. PNa, PK is permeability to Na+ and K+, respectively. (From Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology. McGraw-Hill, 2008.)
Decreasing the external Na+ concentration reduces the size of the action potential but has little effect on the resting membrane potential. The lack of much effect on the resting membrane potential would be predicted, since the permeability of the membrane to Na+ at rest is relatively low. In contrast, since the resting membrane potential is close to the equilibrium potential for K+, changes in the changes in the external concentration of this ion can have major effects on the resting membrane potential. If the extracellular level of K+ is increased (hyperkalemia), the resting potential moves closer to the threshold for eliciting an action potential, thus the neuron becomes more excitable. If the extracellular level of K+ is decreased (hypokalemia), the membrane potential is reduced and the neuron is hyperpolarized.
Although Na+ enters the nerve cell and K+ leaves it during the action potential, very few ions actually move across the membrane. It has been estimated that only 1 in 100,000 K+ ions cross the membrane to change the membrane potential from +30 mV (peak of the action potential) to –70 mV (resting potential). Significant differences in ion concentrations can be measured only after prolonged, repeated stimulation.
Other ions, notably Ca2+, can affect the membrane potential through both channel movement and membrane interactions. A decrease in extracellular Ca2+ concentration increases the excitability of nerve and muscle cells by decreasing the amount of depolarization necessary to initiate the changes in the Na+ and K+ conductance that produce the action potential. Conversely, an increase in extracellular Ca2+ concentration can stabilize the membrane by decreasing excitability.
ALL-OR-NONE ACTION POTENTIALS
It is possible to determine the minimal intensity of stimulating current (threshold intensity) that, acting for a given duration, will just produce an action potential. The threshold intensity varies with the duration; with weak stimuli it is long, and with strong stimuli it is short. The relation between the strength and the duration of a threshold stimulus is called the strength–duration curve. Slowly rising currents fail to fire the nerve because the nerve adapts to the applied stimulus, a process called adaptation.
Once threshold intensity is reached, a full-fledged action potential is produced. Further increases in the intensity of a stimulus produce no increment or other change in the action potential as long as the other experimental conditions remain constant. The action potential fails to occur if the stimulus is subthreshold in magnitude, and it occurs with constant amplitude and form regardless of the strength of the stimulus if the stimulus is at or above threshold intensity. The action potential is therefore all-or-none in character.
ELECTROTONIC POTENTIALS, LOCAL RESPONSE, & FIRING LEVEL
Although subthreshold stimuli do not produce an action potential, they do have an effect on the membrane potential. This can be demonstrated by placing recording electrodes within a few millimeters of a stimulating electrode and applying subthreshold stimuli of fixed duration. Application of such currents leads to a localized depolarizing potential change that rises sharply and decays exponentially with time. The magnitude of this response drops off rapidly as the distance between the stimulating and recording electrodes is increased. Conversely, an anodal current produces a hyperpolarizing potential change of similar duration. These potential changes are called electrotonic potentials.As the strength of the current is increased, the response is greater due to the increasing addition of a local response of the membrane (Figure 4–8). Finally, at 7–15 mV of depolarization (potential of –55 mV), the firing level(threshold potential) is reached and an action potential occurs.
FIGURE 4–8 Electrotonic potentials and local response. The changes in the membrane potential of a neuron following application of stimuli of 0.2, 0.4, 0.6, 0.8, and 1.0 times threshold intensity are shown superimposed on the same time scale. The responses below the horizontal line are those recorded near the anode, and the responses above the line are those recorded near the cathode. The stimulus of threshold intensity was repeated twice. Once it caused a propagated action potential (top line), and once it did not.
CHANGES IN EXCITABILITY DURING ELECTROTONIC POTENTIALS & THE ACTION POTENTIAL
During the action potential, as well as during electrotonic potentials and the local response, the threshold of the neuron to stimulation changes (Figure 4–6). Hyperpolarizing responses elevate the threshold, and depolarizing potentials lower it as they move the membrane potential closer to the firing level. During the local response, the threshold is lowered, but during the rising and much of the falling phases of the spike potential, the neuron is refractory to stimulation. This refractory period is divided into an absolute refractory period, corresponding to the period from the time the firing level is reached until repolarization is about one-third complete, and a relative refractory period, lasting from this point to the start of after-depolarization. During the absolute refractory period, no stimulus, no matter how strong, will excite the nerve, but during the relative refractory period, stronger than normal stimuli can cause excitation. These changes in threshold are correlated with the phases of the action potential in Figure 4–6.
CONDUCTION OF THE ACTION POTENTIAL
The nerve cell membrane is polarized at rest, with positive charges lined up along the outside of the membrane and negative charges along the inside. During the action potential, this polarity is abolished and for a brief period is actually reversed (Figure 4–9). Positive charges from the membrane ahead of and behind the action potential flow into the area of negativity represented by the action potential (“current sink”). By drawing off positive charges, this flow decreases the polarity of the membrane ahead of the action potential. Such electrotonic depolarization initiates a local response, and when the firing level is reached, a propagated response occurs that in turn electrotonically depolarizes the membrane in front of it.
FIGURE 4–9 Local current flow (movement of positive charges) around an impulse in an axon. Top: Unmyelinated axon. Bottom: Myelinated axon. Positive charges from the membrane ahead of and behind the action potential flow into the area of negativity represented by the action potential (“current sink”). In myelinated axons, depolarization appears to “jump” from one node of Ranvier to the next (saltatory conduction).
The spatial distribution of ion channels along the axon plays a key role in the initiation and regulation of the action potential. Voltage-gated Na+ channels are highly concentrated in the nodes of Ranvier and the initial segment in myelinated neurons. The number of Na+ channels per square micrometer of membrane in myelinated mammalian neurons has been estimated to be 50–75 in the cell body, 350–500 in the initial segment, less than 25 on the surface of the myelin, 2000–12,000 at the nodes of Ranvier, and 20–75 at the axon terminals. Along the axons of unmyelinated neurons, the number is about 110. In many myelinated neurons, the Na+ channels are flanked by K+ channels that are involved in repolarization.
Conduction in myelinated axons depends on a similar pattern of circular current flow as described above. However, myelin is an effective insulator, and current flow through it is negligible. Instead, depolarization in myelinated axons travels from one node of Ranvier to the next, with the current sink at the active node serving to electrotonically depolarize the node ahead of the action potential to the firing level (Figure 4–9). This “jumping” of depolarization from node to node is called saltatory conduction. It is a rapid process that allows myelinated axons to conduct up to 50 times faster than the fastest unmyelinated fibers.
ORTHODROMIC & ANTIDROMIC CONDUCTION
An axon can conduct in either direction. When an action potential is initiated in the middle of the axon, two impulses traveling in opposite directions are set up by electrotonic depolarization on either side of the initial current sink. In the natural situation, impulses pass in one direction only, ie, from synaptic junctions or receptors along axons to their termination. Such conduction is called orthodromic. Conduction in the opposite direction is called antidromic.Because synapses, unlike axons, permit conduction in one direction only, an antidromic impulse will fail to pass the first synapse they encounter and die out at that point.
PROPERTIES OF MIXED NERVES
Peripheral nerves in mammals are made up of many axons bound together in a fibrous envelope called the epineurium. Potential changes recorded extracellularly from such nerves therefore represent an algebraic summation of the all-or-none action potentials of many axons. The thresholds of the individual axons in the nerve and their distance from the stimulating electrodes vary. With subthreshold stimuli, none of the axons are stimulated and no response occurs. When the stimuli are of threshold intensity, axons with low thresholds fire and a small potential change is observed. As the intensity of the stimulating current is increased, the axons with higher thresholds are also discharged. The electrical response increases proportionately until the stimulus is strong enough to excite all of the axons in the nerve. The stimulus that produces excitation of all the axons is the maximal stimulus, and application of greater, supramaximal stimuli produces no further increase in the size of the observed potential.
After a stimulus is applied to a nerve, there is a latent period before the start of the action potential. This interval corresponds to the time it takes the impulse to travel along the axon from the site of stimulation to the recording electrodes. Its duration is proportionate to the distance between the stimulating and recording electrodes and inversely proportionate to the speed of conduction. If the duration of the latent period and the distance between the stimulating and recording electrodes are known, axonal conduction velocity can be calculated.
NERVE FIBER TYPES & FUNCTION
Erlanger and Gasser divided mammalian nerve fibers into A, B, and C groups, further subdividing the A group into α, β, γ, and δ fibers. In Table 4–1, the various fiber types are listed with their diameters, electrical characteristics, and functions. By comparing the neurologic deficits produced by careful dorsal root section and other nerve-cutting experiments with the histologic changes in the nerves, the functions and histologic characteristics of each of the families of axons responsible for the various peaks of the compound action potential have been established. In general, the greater the diameter of a given nerve fiber, the greater is its speed of conduction. The large axons are concerned primarily with proprioceptive sensation, somatic motor function, conscious touch, and pressure, while the smaller axons subserve pain and temperature sensations and autonomic function.
TABLE 4–1 Types of mammalian nerve fibers.
Further research has shown that not all the classically described lettered components are homogeneous, and a numerical system (Ia, Ib, II, III, and IV) has been used by some physiologists to classify sensory fibers. Unfortunately, this has led to confusion. A comparison of the number system and the letter system is shown in Table 4–2.
TABLE 4–2 Numerical classification of sensory nerve fibers.
In addition to variations in speed of conduction and fiber diameter, the various classes of fibers in peripheral nerves differ in their sensitivity to hypoxia and anesthetics (Table 4–3). This fact has clinical as well as physiologic significance. Local anesthetics depress transmission in the group C fibers before they affect group A touch fibers (see Clinical Box 4–2). Conversely, pressure on a nerve can cause loss of conduction in large-diameter motor, touch, and pressure fibers while pain sensation remains relatively intact. Patterns of this type are sometimes seen in individuals who sleep with their arms under their heads for long periods, causing compression of the nerves in the arms. Because of the association of deep sleep with alcoholic intoxication, the syndrome is most common on weekends and has acquired the interesting name Saturday night or Sunday morning paralysis.
TABLE 4–3 Relative susceptibility of mammalian A, B, and C nerve fibers to conduction block produced by various agents.
CLINICAL BOX 4–2
Local or regional anesthesia is used to block the conduction of action potentials in sensory and motor nerve fibers. This usually occurs as a result of blockade of voltage-gated Na+ channels on the nerve cell membrane. This causes a gradual increase in the threshold for electrical excitability of the nerve, a reduction in the rate of rise of the action potential, and a slowing of axonal conduction velocity. There are two major categories of local anesthetics: ester-linked (eg, cocaine, procaine, tetracaine) or amide-linked (eg, lidocaine, bupivacaine). In addition to either the ester or amide, all local anesthetics contain an aromatic and an amine group. The structure of the aromatic group determines the drug’s hydrophobic characteristics, and the amine group determines its latency to onset of action and its potency. Application of these drugs into the vicinity of a central (eg, epidural, spinal anesthesia) or peripheral nerve can lead to rapid, temporary, and near complete interruption of neural traffic to allow a surgical or other potentially noxious procedure to be done without eliciting pain. Cocaine (from the coca shrub, Erythroxylan coca) was the first chemical to be identified as having local anesthetic properties and remains the only naturally occurring local anesthetic. In 1860, Albert Niemann isolated the chemical, tasted it, and reported a numbing effect on his tongue. The first clinical use of cocaine as a local anesthetic was in 1886 when Carl Koller used it as a topical ophthalmic anesthetic. Its addictive and toxic properties prompted the development of other local anesthetics. In 1905, procaine was synthesized as the first suitable substitute for cocaine. Nociceptive fibers (unmyelinated C fibers) are the most sensitive to the blocking effect of local anesthetics. This is followed by sequential loss of sensitivity to temperature, touch, and deep pressure. Motor nerve fibers are the most resistant to the actions of local anesthetics.
A number of proteins necessary for survival and growth of neurons have been isolated and studied. Some of these neurotrophins are products of the muscles or other structures that the neurons innervate, but many in the CNS are produced by astrocytes. These proteins bind to receptors at the endings of a neuron. They are internalized and then transported by retrograde transport to the neuronal cell body, where they foster the production of proteins associated with neuronal development, growth, and survival. Other neurotrophins are produced in neurons and transported in an anterograde fashion to the nerve ending, where they maintain the integrity of the postsynaptic neuron.
Four established neurotrophins and their three high-affinity tyrosine kinase associated (Trk) receptors are listed in Table 4–4. Each of these Trk receptors dimerizes, and this initiates autophosphorylation in the cytoplasmic tyrosine kinase domains of the receptors. An additional low-affinity NGF receptor that is a 75-kDa protein is called p75NTR. This receptor binds all four of the listed neurotrophins with equal affinity. There is some evidence that it can form a heterodimer with Trk A monomer and that the dimer has increased affinity and specificity for NGF. However, it now appears that p75NTR receptors can form homodimers that in the absence of Trk receptors cause apoptosis, an effect opposite to the usual growth-promoting and nurturing effects of neurotrophins. Research is ongoing to characterize the distinct roles of p75NTR and Trk receptors and factors that influence their expression in neurons.
TABLE 4–4 Neurotrophins.
FUNCTION OF NEUROTROPHINS
The first neurotrophin to be characterized was NGF, a protein growth factor that is necessary for the growth and maintenance of sympathetic neurons and some sensory neurons. It is present in a broad spectrum of animal species, including humans, and is found in many different tissues. In male mice, there is a particularly high concentration in the submandibular salivary glands, and the level is reduced by castration to that seen in females. The factor is made up of two α, two β, and two γ subunits. The β subunits, each of which has a molecular mass of 13,200 Da, have all the nerve growth-promoting activity, the α subunits have trypsin-like activity, and the γ subunits are serine proteases. The function of the proteases is unknown. The structure of the β subunit of NGF resembles that of insulin.
NGF is picked up by neurons and is transported in retrograde fashion from the endings of the neurons to their cell bodies. It is also present in the brain and appears to be responsible for the growth and maintenance of cholinergic neurons in the basal forebrain and the striatum. Injection of antiserum against NGF in newborn animals leads to almost total destruction of the sympathetic ganglia; it thus produces an immunosympathectomy. There is evidence that the maintenance of neurons by NGF is due to a reduction in apoptosis.
Brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), NT-4/5, and NGF each maintain a different pattern of neurons, although there is some overlap. Disruption of NT-3 by gene knockout causes a marked loss of cutaneous mechanoreceptors, even in heterozygotes. BDNF acts rapidly and can actually depolarize neurons. BDNF-deficient mice lose peripheral sensory neurons and have severe degenerative changes in their vestibular ganglia and blunted long-term potentiation.
OTHER FACTORS AFFECTING NEURONAL GROWTH
The regulation of neuronal growth is a complex process. Schwann cells and astrocytes produce ciliary neurotrophic factor (CNTF). This factor promotes the survival of damaged and embryonic spinal cord neurons and may prove to be of value in treating human diseases in which motor neurons degenerate. Glial cell line-derived neurotrophic factor (GDNF) maintains midbrain dopaminergic neurons in vitro. However, GDNF knockouts have dopaminergic neurons that appear normal, but they have no kidneys and fail to develop an enteric nervous system. Another factor that enhances the growth of neurons is leukemia inhibitory factor (LIF). In addition, neurons as well as other cells respond to insulin-like growth factor I (IGF-I) and the various forms of transforming growth factor (TGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF).
Clinical Box 4–3 compares the ability to regenerate neurons after central and peripheral nerve injury.
CLINICAL BOX 4–3
Peripheral nerve damage is often reversible. Although the axon will degenerate distal to the damage, connective elements of the so-called distal stump often survive. Axonal sprouting occurs from the proximal stump, growing toward the nerve ending. This results from growth-promoting factors secreted by Schwann cells that attract axons toward the distal stump. Adhesion molecules of the immunoglobulin superfamily (eg, NgCAM/L1) promote axon growth along cell membranes and extracellular matrices. Inhibitory molecules in the perineurium assure that the regenerating axons grow in a correct trajectory. Denervated distal stumps are able to upregulate production of neurotrophins that promote growth. Once the regenerated axon reaches its target, a new functional connection (eg, neuromuscular junction) is formed. Regeneration allows for considerable, although not full, recovery. For example, fine motor control may be permanently impaired because some motor neurons are guided to an inappropriate motor fiber. Nonetheless, recovery of peripheral nerves from damage far surpasses that of central nerve pathways. The proximal stump of a damaged axon in the CNS will form short sprouts, but distant stump recovery is rare, and the damaged axons are unlikely to form new synapses. This is in part because CNS neurons do not have the growth-promoting chemicals needed for regeneration. In fact, CNS myelin is a potent inhibitor of axonal growth. In addition, following CNS injury several events—astrocytic proliferation, activation of microglia, scar formation, inflammation, and invasion of immune cells—provide an inappropriate environment for regeneration. Thus, treatment of brain and spinal cord injuries frequently focuses on rehabilitation rather than reversing the nerve damage. New research is aiming to identify ways to initiate and maintain axonal growth, to direct regenerating axons to reconnect with their target neurons, and to reconstitute original neuronal circuitry.
There is evidence showing that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen can overcome the factors that inhibit axonal growth following injury. This effect is thought to be mediated by the ability of NSAIDs to inhibit RhoA, a small GTPase protein that normally prevents repair of neural pathways and axons. Growth cone collapse in response to myelin-associated inhibitors after nerve injury is prevented by drugs such as pertussis toxin, which interfere with signal transduction via trimeric G protein. Experimental drugs that inhibit the phosphoinositide 3-kinase (PI3) pathway or the inositol triphosphate (IP3) receptor have also been shown to promote regeneration after nerve injury.
There are two main types of glia: microglia and macroglia. Microglia are scavenger cells. Macroglia include oligodendrocytes, Schwann cells, and astrocytes. The first two are involved in myelin formation; astrocytes produce substances that are tropic to neurons, and they help maintain the appropriate concentration of ions and neurotransmitters.
Neurons are composed of a cell body (soma) that is the metabolic center of the neuron, dendrites that extend outward from the cell body and arborize extensively, and a long fibrous axon that originates from a somewhat thickened area of the cell body, the axon hillock.
The axons of many neurons acquire a sheath of myelin, a protein–lipid complex that is wrapped around the axon. Myelin is an effective insulator, and depolarization in myelinated axons travels from one node of Ranvier to the next, with the current sink at the active node serving to electrotonically depolarize to the firing level the node ahead of the action potential.
Orthograde transport occurs along microtubules that run the length of the axon and requires two molecular motors: dynein and kinesin. It moves from the cell body toward the axon terminals and has both fast (400 mm/day) and slow (0.5–10 mm/day) components. Retrograde transport, which is in the opposite direction (from the nerve ending to the cell body), occurs along microtubules at about 200 mm/day.
In response to a depolarizing stimulus, voltage-gated Na+ channels become active, and when the threshold potential is reached, an action potential results. The membrane potential moves toward the equilibrium potential for Na+. The Na+ channels rapidly enter a closed state (inactivated state) before returning to the resting state. The direction of the electrical gradient for Na+ is reversed during the overshoot because the membrane potential is reversed, and this limits Na+ influx. Voltage-gated K+ channels open and the net movement of positive charge out of the cell helps complete the process of repolarization. The slow return of the K+ channels to the closed state explains after-hyperpolarization, followed by a return to the resting membrane potential.
Nerve fibers are divided into different categories (A, B, and C) based on axonal diameter, conduction velocity, and function. A numerical classification (Ia, Ib, II, III, and IV) is also used for sensory afferent fibers.
Neurotrophins such as NGF are carried by retrograde transport to the neuronal cell body, where they foster the production of proteins associated with neuronal development, growth, and survival.
For all questions, select the single best answer unless otherwise directed.
1. Which of the following statements about glia is true?
A. Microglia arise from macrophages outside of the nervous system and are physiologically and embryologically similar to other neural cell types.
B. Glia do not undergo proliferation.
C. Protoplasmic astrocytes produce substances that are tropic to neurons to help maintain the appropriate concentration of ions and neurotransmitters by taking up K+ and the neurotransmitters glutamate and GABA.
D. Oligodendrocytes and Schwann cells are involved in myelin formation around axons in the peripheral and central nervous systems, respectively.
E. Macroglia are scavenger cells that resemble tissue macrophages and remove debris resulting from injury, infection, and disease.
2. A 13-year-old girl was being seen by her physician because of experiencing frequent episodes of red, painful, warm extremities. She was diagnosed with primary erythromelalgia, which may be due to a peripheral nerve sodium channelopathy. Which part of a neuron has the highest concentration of Na+ channels per square micrometer of cell membrane?
B. cell body near dendrites
C. initial segment
D. axonal membrane under myelin
E. none of Ranvier
3. A 45-year-old female office worker had been experiencing tingling in her index and middle fingers and thumb of her right hand. Recently, her wrist and hand had become weak. Her physician ordered a nerve conduction test to evaluate her for carpal tunnel syndrome. Which one of the following nerves has the slowest conduction velocity?
A. Aα fibers
B. Aβ fibers
C. Aγ fibers
D. B fibers
E. C fibers
4. Which of the following is not correctly paired?
A. Synaptic transmission: Antidromic conduction
B. Molecular motors: Dynein and kinesin
C. Fast axonal transport: ˜400 mm/day
D. Slow axonal transport: 0.5–10 mm/day
E. Nerve growth factor: Retrograde transport
5. A 32-year-old female received an injection of a local anesthetic for a tooth extraction. Within 2 h, she noted palpitations, diaphoresis, and dizziness. Which of the following ionic changes is correctly matched with a component of the action potential?
A. Opening of voltage-gated K+ channels: After-hyperpolarization
B. A decrease in extracellular Ca2+: Repolarization
C. Opening of voltage-gated Na+ channels: Depolarization
D. Rapid closure of voltage-gated Na+ channels: Resting membrane potential
E. Rapid closure of voltage-gated K+ channels: Relative refractory period
6. A man falls into a deep sleep with one arm under his head. This arm is paralyzed when he awakens, but it tingles, and pain sensation in it is still intact. The reason for the loss of motor function without loss of pain sensation is that in the nerves to his arm,
A. A fibers are more susceptible to hypoxia than B fibers.
B. A fibers are more sensitive to pressure than C fibers.
C. C fibers are more sensitive to pressure than A fibers.
D. Motor nerves are more affected by sleep than sensory nerves.
E. Sensory nerves are nearer the bone than motor nerves and hence are less affected by pressure.
7. Which of the following statements about nerve growth factor is not true?
A. It is made up of three polypeptide subunits.
B. It is responsible for the growth and maintenance of adrenergic neurons in the basal forebrain and the striatum.
C. It is necessary for the growth and development of the sympathetic nervous system.
D. It is picked up by nerves from the organs they innervate.
E. It can express both p75NTR and Trk A receptors.
8. A 20-year old female student awakens one morning with severe pain and blurry vision in her left eye; the symptoms abate over several days. About 6 months later, on a morning after playing volleyball with friends, she notices weakness but not pain in her right leg; the symptoms intensify while taking a hot shower. Which of the following is most likely to be the case?
A. The two episodes described are not likely to be related.
B. She may have primary-progressive multiple sclerosis.
C. She may have relapsing-remitting multiple sclerosis.
D. She may have a lumbar disk rupture.
E. She may have Guillain–Barre syndrome.
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