EXCITABLE TISSUE; NERVE.pdf

CHAPTER 4 Excitable Tissue: Nerve OBJECTIVES After studying this chapter, you should be able to: Draw a typical neuron and identify the role played by soma, dendrites, axon, and initial segment in impulse generation and conduction. Explain the basis for the resting membrane potential of a ne...

CHAPTER 4 Excitable Tissue: Nerve OBJECTIVES After studying this chapter, you should be able to: Draw a typical neuron and identify the role played by soma, dendrites, axon, and initial segment in impulse generation and conduction. Explain the basis for the resting membrane potential of a neuron and the effect of hyperkalemia and hypokalemia on the resting potential. Explain the ionic fluxes that occur during an action potential. Compare and contrast how unmyelinated and myelinated neurons propagate impulses. Compare the conduction velocity and other properties of different types of sensory and motor nerve fibers. Explain the importance of orthograde and retrograde axonal transport. Compare the functions of the various types of glia found in the nervous system. Identify neuropathologies related to dysfunction of myelin proteins or the loss of myelin. Describe the function of neurotrophins. INTRODUCTION The basic working unit of the central and peripheral nervous system is the nerve cell or neuron. Neurons are identified as excitable cells because they have the ability to be electrically excited resulting in the generation of action potentials. Other examples of excitable cells are skeletal, smooth, and cardiac muscle cells (Chapter 5) and secretory cells of the pancreas. Neurons come in many different shapes and sizes, but they share features that impart in them an ability to receive, process, integrate, and transmit information from external and internal sources to initiate most physiological behaviors. This chapter describes the ionic mechanisms that enable neurons to generate and conduct impulses; Chapter 6 explains how neurons communicate with other neurons and effector organs (synaptic transmission). This chapter also describes the roles played by neuroglia cells and neurotrophins in physiological and pathophysiological processes. THE NEURON: BASIC WORKING UNIT OF THE NERVOUS SYSTEM Figure 4–1 shows the basic components of a neuron for the prototypical spinal motor neuron. The cell body (soma) contains the nucleus that is the metabolic center of the neuron and stores the hereditary material or DNA. Neurons have several processes called dendrites that extend outward from the cell body and arborize extensively to aid their role in receiving incoming signals, processing the information, and then transmitting the information to the soma of the neuron. A typical neuron also has a long fibrous axon that originates from a thickened area of the cell body (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 that are also called terminal buttons or boutons. They contain granules or vesicles in which the synaptic transmitters released by the nerves are stored. Based on the number of processes that emanate from their cell body, neurons can be classified as unipolar, bipolar, pseudounipolar, and multipolar (Figure 4–2). FIGURE 4–1 Motor neuron with a myelinated axon. A motor neuron is composed 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 4–2 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 pseudounipolar 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. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM, Siegelbaum SA, Hudspeth AJ (editors): Principles of Neural Science, 5th ed. New York, NY: McGraw-Hill; 2013.) From a functional point of view, neurons generally have four important zones: (1) a 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 axons of many neurons acquire a myelin sheath, a protein–lipid complex that is wrapped around the axon. In the peripheral nervous system, myelin forms when a Schwann cell (a type of glia) wraps its membrane around an axon up to 100 times (Figure 4–1). The myelin sheath envelops the axon except at the nodes of Ranvier, periodic 1-µm gaps where the axon is unmyelinated (Figure 4–1). The insulating function of myelin and its role in axonal conduction are discussed later in this chapter. EXCITATION & CONDUCTION A hallmark of nerve cells is their excitable membrane. Neurons respond to electrical, chemical, or mechanical stimuli by producing local (nonpropagated) or propagated potentials reflecting changes in the conduction of ions across the cell membrane. Depending on their location, the nonpropagated potentials are called synaptic, generator, or electrotonic potentials. The propagated action potentials are the primary electrical responses of neurons; they are the main form of communication within the nervous system. The electrical events in neurons are rapid, measured in milliseconds (ms); and the potential changes are small, measured in millivolts (mV). The impulse is normally transmitted (conducted) along the axon to its termination. 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 The voltage difference across the cell membrane of a neuron is called a membrane potential; it is the difference between the electrical potential in the cytoplasm of the cell and the electrical potential in the extracellular space. The membrane potential results from the separation of positive and negative charges across the cell membrane (Figure 4–3). 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 type across the membrane (ie, a concentration gradient). Second, the membrane must be permeable to these ions. The permeability is provided by the existence of channels or pores in the bilayer; these channels are usually permeable to a single type of ion. FIGURE 4–3 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. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM, Siegelbaum SA, Hudspeth AJ (editors): Principles of Neural Science, 5th ed. New York, NY: McGraw-Hill; 2013.) 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. The resting membrane potential of neurons is usually about –70 mV (step 1 in Figure 4–4). 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. Na, K ATPase prevents this from occurring by actively moving Na+ and K+ against their electrochemical gradients. FIGURE 4–4 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 with permission from Silverthorn DU: Human Physiology: An Integrated Approach, 5th ed. Pearson, 2010.) IONIC FLUXES DURING THE ACTION POTENTIAL Neuronal cell membranes contain many types of ion channels, including both ligand-gated and voltage-gated ion channels. Ligand-gated ion channels open when a ligand (eg, neurotransmitter) binds to them, and voltage-gated ion channels open when there is a change in the voltage gradient across the membrane. The behavior of these channels, particularly Na+ and K+ channels, explains the electrical events in neurons. The changes in membrane conductance of Na+ and K+ that occur during an action potential are shown by steps 1 through 7 in Figure 4–4. 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. The direction of the electrical gradient for Na+ is reversed during the overshoot because the membrane potential is reversed which 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; 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 4–5 shows the sequential feedback control in voltage-gated K+ and Na+ channels during the action potential. FIGURE 4–5 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. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology. New York, NY: 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 is predicted because 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 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 and the neuron becomes more excitable. If the extracellular level of K+ is decreased (hypokalemia), the membrane potential is reduced and the neuron is hyperpolarized. Clinical Box 4–1 describes some of the common causes, signs, and treatments for the deviation of plasma levels of K+ away from the normal value of 3.5–5.0 mEq/L on excitable cells (eg, neurons, heart, skeletal muscle, smooth muscle). 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 needed 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 reducing excitability. ALL-OR-NONE ACTION POTENTIALS The minimal intensity of stimulating current needed to produce an action potential is called the threshold intensity; it varies with the stimulus duration. A weak stimulus needs a long duration, and a strong stimulus is sufficient at a short duration. The relation between the strength and the duration of a threshold stimulus is called the strength–duration curve. Slowly rising currents fail to induce an action potential in the nerve because the nerve undergoes adaptation. The action potential is all-or-none in character. That is, no action potential occurs if the stimulus is subthreshold in magnitude, and the action potential has a constant amplitude and form at any stimulus strength above the threshold intensity. CLINICAL BOX 4–1  Hyperkalemia and Hypokalemia Potassium homeostasis is critical for the normal functioning of nerves, skeletal muscle, smooth muscle, and the heart. A primary cause of hyperkalemia is impairment in the ability of the kidney to excrete K+ due to advanced renal failure, adrenal insufficiency, distal renal tubular acidosis, type 1 diabetes, and dehydration. Drug-induced hyperkalemia can result from the use of angiotensin II receptor blockers, angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and potassium sparing diuretics. Symptoms of hyperkalemia include muscle pain and weakness, numbness, cardiac arrhythmias, and nausea. Extremely high levels of plasma K+ can lead to cardiac arrest and death. Hyperkalemic periodic paralysis is a rare inherited disorder (prevalence of 1 per 100,000 individuals) in which patients experience transient episodes of muscle paralysis due to hyperkalemia. The resting membrane potential of skeletal muscle in affected individuals shifts from a normal value of −90 mV to a value of −60 mV which inactivates Na+ channels and prevents action potential generation. The most common cause of hypokalemia is increased excretion of K+, but it can also occur if there is a shift of K+ from the extracellular to the intracellular space. Hypokalemia can be a side effect of rare genetic disorders of the kidney (Bartter syndrome [see Chapter 37] and Gitelman syndrome), Cushing syndrome, the use of K+-wasting diuretics, diabetic ketoacidosis, renal tubular acidosis, and familial hypokalemia. Symptoms are somewhat nonspecific but can include weakness and fatigue, constipation, muscle cramping, palpitations, and psychological symptoms such as depression or psychosis. Severe hypokalemia (below 2.5 mEq/L) mainly leads to problems with cardiac rhythmicity and can manifest as bradycardia, tachycardia, premature beats, and atrial or ventricular fibrillation. THERAPEUTIC HIGHLIGHTS Treatment of hyperkalemia typically includes treatment of the underlying cause. It may also include a low-potassium diet, intravenous administration of calcium to protect the heart and muscles, or administration of sodium bicarbonate to promote movement of K+ from the extracellular space back into the cells. Treatment of hypokalemia focuses on ways to reduce K+ loss (eg, discontinue the use of a diuretic or use a K+-sparing diuretic), replenish K+ stores (oral or intravenous administration of K+), and determining and treating the cause of the hypokalemia. ELECTROTONIC POTENTIALS, LOCAL RESPONSE, & FIRING LEVEL Although subthreshold stimuli do not produce a propagating action potential, they do have an effect on the membrane potential. Applying subthreshold stimuli of fixed duration leads to a localized depolarizing potential change that rises sharply and decays exponentially with time (Figure 4–6). The magnitude of this response drops off rapidly as the distance between the stimulating and recording electrode 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. Finally, at 7–15 mV of depolarization (potential of –55 mV), the threshold potential is reached and an action potential occurs. FIGURE 4–6 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. REFRACTORY PERIODS During the action potential, as well as during electrotonic potentials and the local response, the threshold of the neuron to stimulation changes (Figure 4–4). Hyperpolarizing responses elevate the threshold, and depolarizing potentials lower it as they move the membrane potential closer to the threshold potential. 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. The 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. However, 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 4–4. 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 4–7). 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 4–7 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 is 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 just described. 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 4–7). 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. NERVE FIBER TYPES & FUNCTION Mammalian nerve fibers are divided into A, B, and C groups, and the A group can be subdivided into α, β, γ, and δ fibers. In Table 4–1, the various fiber types are listed with their diameters, electrical characteristics, and functions. 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. In general, the greater the diameter of a given nerve fiber, the greater 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. Although the letter classification is commonly used to describe motor fibers, a numerical system (Ia, Ib, II, III, and IV) is often used to classify sensory fibers based on their axonal diameter and conduction velocity. Table 4–2 shows the corresponding classification of the number system and the letter system. 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 unmyelinated group C fibers before they affect the myelinated group A fibers (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. AXONAL TRANSPORT The apparatus for protein synthesis in neurons is located primarily in the soma, 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. Orthograde transport occurs along microtubules located along the length of the axon; it requires two molecular motors, dynein and kinesin (Figure 4–8). 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 0.5–10 mm/day. Retrograde transport from the nerve ending to the cell body occurs 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. FIGURE 4–8 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. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology. New York, NY: McGraw-Hill; 2008.) GLIA The word glia is Greek for glue. For many years following their discovery, neuroglia cells were viewed as connective tissue. Today these cells are recognized for their role in communication within the central nervous system (CNS) in partnership with neurons. Unlike most neurons, glia continue to undergo cell division in adulthood and their ability to proliferate is particularly noticeable after brain injury (eg, stroke). Glia are classified as microglia and macroglia depending on their size. Microglia are part of the immune system; they are scavenger cells that resemble tissue macrophages and remove debris resulting from injury, infection, and disease (eg, multiple sclerosis [MS], 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 4–9). Oligodendrocytes and Schwann cells are involved in myelin formation around axons in the CNS and peripheral nervous system, respectively. Unlike the Schwann cell, which forms the myelin on a single axon (Figure 4–1), oligodendrocytes emit multiple processes that form myelin on many neighboring axons. In MS, patchy destruction of myelin occurs in the CNS (Clinical Box 4–3). The loss of myelin is associated with delayed or blocked conduction in the demyelinated axons. Myelin protein zero (P0) and a hydrophobic protein PMP22 are components of the myelin sheath in the peripheral nervous system. Autoimmune reactions to these proteins cause Guillain–Barré syndrome, a peripheral demyelinating neuropathy. Mutations in myelin protein genes cause peripheral neuropathies that disrupt myelin and cause axonal degeneration (eg, Charcot-Marie-Tooth disease). FIGURE 4–9 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. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM, Siegelbaum SA, Hudspeth AJ (editors): Principles of Neural Science, 5th ed. New York, NY: McGraw-Hill; 2013.) Astrocytes are found throughout the brain and are subdivided into two groups. Fibrous astrocytes are found primarily in white matter and contain many intermediate filaments; protoplasmic astrocytes are found in gray matter and have a granular cytoplasm. Both types of astrocytes 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).  CLINICAL BOX 4–2 Local Anesthesia 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. Its addictive and toxic properties prompted the development of other local anesthetics. 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. NEUROTROPHINS: THEIR FUNCTION & RECEPTORS Neurotrophins are necessary for survival and growth of neurons. Some of them are products of 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 soma and transported to the nerve ending where they maintain the integrity of the postsynaptic neuron. NGF, the first neurotrophin identified, is a protein growth factor that is needed for the growth and maintenance of sympathetic neurons and some sensory neurons. NGF 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 transported in a retrograde fashion from the nerve endings to the cell body. NGF may be responsible for the growth and maintenance of cholinergic neurons in the basal forebrain and the striatum. NGF-mediated survival of neurons is due to suppression of apoptosis rather than promotion of cell metabolism. In addition to NGF, there are other neurotrophins, including brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and NT-4/5. They each maintain a different pattern of neurons, although there is some overlap. NT-3 is important for proprioceptor neurons that innervate the muscle spindle and mechanoreceptors in the skin; NT-4/5 is important for neurons that innervate the hair follicle; NGF is important for skin nociceptive neurons. Sympathetic neurons depend on both NGF and NT-3. 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. These 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 initiates phosphorylation in the cytoplasmic tyrosine kinase domains of the receptors. An additional low-affinity NGF receptor that is a 75-kDa protein is called the p75 receptor. This receptor binds all four of the listed neurotrophins with equal affinity. Interestingly, if a p75 receptor becomes activated in the absence of exposure to a neurotrophin, it causes apoptosis or cell death, an effect opposite to the usual growth-promoting and nurturing effects of neurotrophins. Research is ongoing to characterize the distinct roles of p75 and Trk receptors and factors that influence their expression in neurons. TABLE 4–4 Neurotrophins. CLINICAL BOX 4–3 Demyelinating Diseases Normal conduction of action potentials relies on the insulating properties of myelin. Thus, defects in myelin can have major adverse neurologic consequences. One example is 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 causes of MS include both genetic and environmental factors. It is most common among whites 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, chickenpox, 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 increased ambient temperature. Progression of the disease is 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. A steadily worsening course with  only minor periods of remission (secondary-progressive MS) develops later in many individuals. 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. THERAPEUTIC HIGHLIGHTS 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 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 younger than 51 years in whom the primary-progressive form of MS was diagnosed. Another clinical trial has shown that oral administration of fingolimod slowed 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. In 2017, the Food and Drug Administration approved the use of ocrelizumab for the treatment of primary-progressive MS; it is an immunosuppressive agent that targets the CD20 marker on B lymphocytes. CLINICAL BOX 4–4 Axonal Regeneration 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, the neuron-glia cell adhesion molecule or NgCAM/L1) promote axon growth along cell membranes and extracellular matrices. Inhibitory molecules in the perineurium ensure 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, allowing 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, after a CNS injury, astrocytic proliferation, activation of microglia, scar formation, inflammation, and invasion of immune cells create an inappropriate environment for regeneration. Thus, treatment of brain and spinal cord injuries 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. THERAPEUTIC HIGHLIGHTS There is evidence showing that the use of NSAIDs such as 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) that 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. 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 the survival of midbrain dopaminergic neurons and prevents the apoptosis of spinal motor neurons. 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 4–4 compares the ability to regenerate neurons after central and peripheral nerve injury. CHAPTER SUMMARY Neurons are composed of a cell body (soma) that is the metabolic center of the neuron, dendrites that extend arborize extensively and are a common zone for receiving input to the neuron, the initial segment of the axon where the action potential is initiated, and a long axon that conducts the action potentials. The resting membrane potential of neurons is about –70 mV, which is close to the equilibrium potential for K+. During hyperkalemia, the resting potential moves closer to the threshold for eliciting an action potential, thus the neuron becomes more excitable. During hypokalemia, the resting membrane potential is reduced and the neuron is hyperpolarized. In response to a depolarizing stimulus, voltage-gated Na+ channels are activated; when the threshold potential is reached, an action potential results. The membrane potential moves toward the equilibrium potential for Na+. The Na+ channels are rapidly inactivated 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; this limits Na+  influx. Voltage-gated K+ channels open to 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. The axons of many neurons are wrapped in myelin, a protein-lipid complex that is an effective insulator; depolarization of 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. 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. These various classes differ in their sensitivity to hypoxia and anesthetics. 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 goes in the opposite direction (from nerve ending to cell body) at a rate of about 200 mm/day. There are two main types of glia: microglia and macroglia. Microglia are scavenger cells. Macroglia include oligodendrocytes, Schwann cells, and astrocytes. Oligodendrocytes and Schwann cells are involved in myelin formation; astrocytes produce substances that are tropic to neurons and help maintain the appropriate concentration of ions and neurotransmitters. Patchy destruction of myelin within the CNS associated with multiple sclerosis delays the conduction in axons. Autoimmune reactions to the myelin proteins P0 and PMP22 cause Guillain–Barré syndrome, a peripheral demyelinating neuropathy. Mutations in myelin protein genes cause peripheral neuropathies (eg, Charcot-Marie-Tooth disease). Neurotrophins (eg, NGF) are carried by retrograde transport to the neuronal cell body where they produce proteins associated with neuronal development, growth, and survival and suppress neuronal apoptosis. MULTIPLE-CHOICE QUESTIONS For all questions, select the single best answer unless otherwise directed.