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Nervous Tissue


The human nervous system is composed of perhaps a trillion neurons, each with a large number of interconnections. Some of these neurons possess receptors that are specialized for receiving different types of stimuli (e.g., mechanical, chemical, thermal), which are transduced into nerve impulses that may eventually arrive at specified nerve centers. These impulses are then transmitted to other neurons for processing and are conveyed to higher centers, where these sensations are registered and/or motor responses are initiated.

Anatomically , the nervous system is organized into the central nervous system ( CNS ), brain and spinal cord, and the peripheral nervous system ( PNS ), cranial nerves, spinal nerves, and their corresponding ganglia. It should be understood that the CNS and PNS are connected to each other.

Functionally , the PNS is divided into a sensory ( afferent ) component , which receives information and transmits impulses to the CNS for processing, and a motor ( efferent ) component , which originates in the CNS and transmits impulses to effector organs throughout the body.

The motor component has two subdivisions: the somatic system ( voluntary system ) where impulses originating in the CNS are transmitted directly, via a single neuron, to skeletal muscles ; and the autonomic system ( involuntary system ), where impulses from the CNS first are transmitted to an autonomic ganglion via one neuron and a second neuron originating in the autonomic ganglion then transmits the impulses to smooth muscles , cardiac muscles , or glands .

In addition to neurons, nervous tissue contains numerous other cells, collectively called neuroglial cells , which, instead of receiving or transmitting impulses, support and assist neurons in various ways.

Development of Nervous Tissue

The nervous system develops from the ectoderm of the embryo in response to signaling molecules from the notochord.

During the early life of the embryo, the notochord releases signaling molecules inducing the overlying ectoderm to form neuroepithelium , which thickens, at first in a uniform fashion, to form the neural plate . Later, as the margins of this plate become thicker, the plate buckles, forming the neural groove whose edges continue to grow toward each other and fuse, forming the neural tube . The rostral (anterior) end of this tube develops into the brain; the remaining (caudal) portion of the neural tube forms the spinal cord. The wall of the neural tube gives rise to neurons, neuroglia, ependyma, and the choroid plexus.

Cells at the lateral margins of the neural plate remain separate from the neural tube, develop into neural crest cells , and early in development migrate away from the neural tube, where they form various derivatives ( Box 9.1 ).

Clinical Correlations

Abnormal organogenesis of the CNS results in various types of congenital malformations. Spina bifida is a defective closure of the spinal column. In severe cases, the spinal cord and meninges may protrude through the unfused areas. Spina bifida anterior is a defective closure of the vertebrae. Severe cases may be associated with defective development of the viscera of the thorax and abdomen.

Anencephaly is failure of the developmental anterior neuropore to close, with a poorly formed brain and absence of the cranial vault. It is usually not compatible with life.

Epilepsy may result from abnormal migration of cortical cells, which disrupts normal interneuronal functioning.

Hirschsprung disease , also known as congenital megacolon , is caused by failure of the neural crest cells to invade the wall of the gut. The wall lacks the Auerbach plexus , a portion of the parasympathetic system innervating the distal end of the colon. Absence of the plexus leads to dilatation and hypertrophy of the colon.

Phenylketonuria (PKU) is a hereditary condition in which the newborn child’s liver is unable to manufacture the enzyme phenylalanine hydroxylase and, therefore, cannot metabolize the essential amino acid phenylalanine. Unless the child is provided with a phenylalanine-free diet, the baby will have mental retardation, seizures, and other intellectual problems. In most developed countries, all newborns are tested for PKU; if present, the mother is placed on a special diet during the period of breastfeeding. It is recommended that the affected individual adhere to a phenylalanine-free diet for life.

BOX 9.1
Derivatives of Neural Crest Cells

Most of the sensory components of the peripheral nervous system

Sensory neurons of cranial and spinal sensory ganglia (dorsal root ganglia)

Autonomic ganglia and the postganglionic autonomic neurons originating in them

Much of the mesenchyme of the anterior head and neck

Melanocytes of the skin and oral mucosa

Odontoblasts (cells responsible for production of dentin)

Chromaffin cells of the adrenal medulla

Cells of the arachnoid and pia mater

Satellite cells of peripheral ganglia

Schwann cells

Cells of the Nervous System

Cells of the nervous system are classified into two categories: neurons and neuroglia.

Neurons and neuroglia are the two categories of cells constituting the nervous system. Neurons perform the receptive, integrative, and motor functions of the nervous system. Neuroglial cells support, protect, and assist neurons in performing their functions.

The Structure and Function of Neurons

Neurons are composed of a cell body, dendrites, and an axon.

Neurons , among the smallest and the largest cells in the body (ranging in diameter from 5 to 150 μm), receive and transmit nerve impulses to and from the CNS. Most neurons are composed of three distinct elements: a cell body , multiple dendrites , and a single axon . The cell body of a neuron, also known as the perikaryon or soma , is the central portion of the cell, housing the nucleus and perinuclear cytoplasm. Neuron cell bodies in the CNS are usually polygonal in shape ( Fig. 9.1 ), with slightly concave surfaces between the many cell processes, whereas neurons in the dorsal root ganglion (a sensory ganglion of the PNS) have a spherical cell body from which only one process exits ( Fig. 9.2 ).

Fig. 9.1, Light micrograph of the gray matter of the spinal cord (×270). Observe the multipolar neuron (mN) cell bodies and their processes.

Fig. 9.2, Light micrograph of a sensory ganglion (×270). Observe the large neuronal cell bodies (N) with singular nucleoli (n).

Projecting from the cell body are one or more dendrites , processes that are specialized for receiving stimuli from sensory cells, axons, and other neurons ( Fig. 9.3 ). Frequently, they are arborized so that they can simultaneously receive multiple stimuli from many other neurons. Nerve impulses received by the dendrites are then transmitted toward the soma.

Fig. 9.3, Motoneuron. (A) Diagram of a typical motor neuron. (B) Electron micrograph of a ventral horn neuron with several of its dendrites (×1300).

Each neuron possesses only one axon , a process that conducts impulses away from the soma to other neurons, muscles, or glands, but it may also receive stimuli from other neurons, which may modify its behavior. Most axons arborize and, usually, each branch has terminal dilatations known as axon terminals ( end bulbs, terminal boutons ) at or near its end. These axon terminals approach other cells to form a synapse , a submicroscopic gap between the axon and the plasma membrane of the target cell where impulses can be transmitted.

Neurons are classified according to their shape and the arrangement of their processes ( Fig. 9.4 ).

Fig. 9.4, Diagram of the various types of neurons.

Neuronal Cell Body (Soma, Perikaryon)

The cell body is the region of the neuron containing the large pale-staining nucleus and perinuclear cytoplasm.

Although the cell body is the most conspicuous region of the neuron, the largest volume of the neuron’s cytoplasm is located in its dendrites and axons. The large, mostly spherical to ovoid nucleus is centrally located in the soma. It contains finely dispersed chromatin, indicative of a rich synthetic activity, although smaller neurons may present some condensed, inactive heterochromatin. A well-defined nucleolus is also common.

The cytoplasm of the cell body has abundant rough endoplasmic reticulum (RER) with many cisternae in parallel arrays, a characteristic especially prominent in large motor neurons. Polyribosomes are also scattered throughout the cytoplasm. When stained with basic dyes, these stacked RER cisternae and polyribosomes appear as clumps of basophilic material, called Nissl bodies , with light microscopy. RER is also present in the dendritic region of the neuron, but is absent at the axon hillock , the region of the cell body where the axon arises.

Most neurons have abundant SER throughout the cell body; this reticulum extends into the dendrites and the axon, forming hypolemmal cisternae directly beneath the plasmalemma. These hypolemmal cisternae are continuous with the RER in the cell body and weave between the Nissl bodies on their way into the dendrites and axon. Although it is unclear how they function, it is known that hypolemmal cisternae sequester calcium and contain protein.

A prominent juxtanuclear Golgi complex is present in the soma, composed of several closely associated cisternae exhibiting dilated peripheries, characteristic of protein-secreting cells. The Golgi complex is also responsible for the packaging of neurotransmitter substances or the enzymes essential for their production in the axon.

The soma, dendrites, and axon are well endowed with mitochondria , but mitochondria are most abundant at the axon terminals. Generally, these mitochondria are more slender than those in other cells and, occasionally, their cristae are oriented longitudinally rather than transversely. Mitochondria of neurons are in constant motion along microtubules in the cytoplasm.

Most adult neurons display only one centriole , which is associated with a basal body of a primary cilium.

Inclusions

Inclusions located in neuronal cell bodies are nonliving substances, such as melanin and lipofuscin pigments as well as lipid droplets.

Dark-brown to black melanin granules are located in some neurons in certain regions of the CNS (e.g., mostly in the substantia nigra and locus ceruleus) and in the sympathetic ganglia of the PNS. The function of these granules in these various locations is unknown. However, dihydroxyphenylalanine, or methyldopa, the precursor of this pigment, is also the precursor of the neurotransmitters dopamine and noradrenaline. Therefore, it has been suggested that melanin may accumulate as a by-product of the synthesis of these neurotransmitters.

Lipofuscin , an irregularly shaped, yellowish-brown pigment granule, is more prevalent in neurons of older adults and is thought to be the remnant of lysosomal enzymatic activity. Lipofuscin granules increase with advancing age and may even crowd the organelles and nucleus to one side in the cell, possibly affecting cellular function. Iron-containing pigments also may be observed in certain neurons of the CNS and may accumulate with age.

Lipid droplets sometimes are observed in the neuronal cytoplasm and may be either the result of faulty metabolism or they may function as energy reserves.

Secretory granules are present in neurosecretory cells; many contain signaling molecules.

Cytoskeletal Components

When prepared by silver impregnation for visualization with light microscopy, the neuronal cytoskeleton exhibits neurofibrils (up to 2 μm in diameter) coursing through the cytoplasm of the soma and extending into the processes. Electron microscopic studies reveal three different filamentous structures: microtubules (24 nm in diameter), neurofilaments (intermediate filaments 10 nm in diameter), and microfilaments (6 nm in diameter). The neurofibrils observed with light microscopy possibly represent clumped bundles of neurofilaments, a suggestion supported by the fact that neurofilaments are stained by silver nitrate. Microfilaments (actin filaments) are associated with the plasma membrane. The microtubules of neurons are identical to those of other cells, except that the microtubule-associated protein-2 (MAP-2) is located in somatic and dendritic cytoplasm, whereas MAP-3 is present in the axon only.

Dendrites

Dendrites receive stimuli from other nerve cells.

Dendrites—and, in some neurons, the cell body and the proximal end of the axon—are elaborations of the receptive plasma membrane. Most neurons have a number of dendrites, each of which arises from the cell body, usually as a single, short trunk that arborizes into increasingly smaller branches, where the specific dendrite branching pattern is characteristic of each particular type of neuron. The base of the dendrite arises from the cell body and contains the usual complement of organelles, especially mitochondria, but with the notable absence of Golgi complexes ( Fig. 9.5 ). Neurofilaments of dendrites are reduced to small bundles or single filaments, which may be cross-linked to microtubules. The branching of dendrites, which results in numerous synaptic terminals, permits a neuron to receive and integrate multiple—perhaps, as in Purkinje cells of the cerebellum, for instance—even hundreds of thousands of impulses. Small bulges, known as spines , located on the surfaces of some dendrites permit them to form synapses with processes of other neurons. The number of these spines diminishes with age and poor nutrition, and they may exhibit structural changes in persons with trisomy 13 and trisomy 21 (Down syndrome) and other anomalous conditions. Dendrites sometimes contain vesicles and are able to transmit impulses to other dendrites.

Fig. 9.5, Diagram of the ultrastructure of a neuronal cell body.

Axons

Axons transmit impulses to other neurons or effector cells, namely, muscle and glands.

The axon arises from the cell body at the axon hillock, a pyramid-shaped region of the soma devoid of ribosomes and usually located on the opposite side of the soma from the dendrites, as a single thin process, usually extending for much longer distances from the cell body than do the dendrites. In some instances, axons of motoneurons may be 1 m or even more in length. Axon thickness varies with the type of neuron, being relatively constant for a particular neuron. Thickness is directly related to conduction velocity so that the thicker the diameter, the faster the conduction velocity. Axons may possess branches, known as collateral branches , which arise at right angles from the axonal trunk (see Fig. 9.3A ). As the axon terminates, it may ramify, forming many small branches ( terminal arbor ).

The portion of the axon from its origin at the axon hillock to the beginning of the myelin sheath is called the initial segment . Deep to the axolemma (plasmalemma of the axon) of the initial segment, when viewed with the electron microscope, a thin, electron-dense layer is visible whose function is not known but resembles the layer located at the nodes of Ranvier (see section on astrocytes). This area of the neuron lacks RER and ribosomes but houses abundant microtubules and neurofilaments that are believed to facilitate the regulation of the axon’s diameter. In some neurons, the number of neurofilaments may increase threefold in the initial segment, whereas the number of microtubules increases only slightly. It is in this initial segment, also referred to as the spike trigger zone , where excitatory and inhibitory impulses are summed to determine whether propagation of an action potential is to occur (see section on generation and conduction of nerve impulses).

The axoplasm (the cytoplasm within the axon) contains short profiles of SER, many microtubules, and remarkably long, thin mitochondria. The axon lacks RER and polyribosomes; therefore, it relies on the soma for its maintenance. Microtubules are grouped in small bundles at the origin of the axon and in the initial segment. Distally, however, they become arranged as uniformly spaced, single microtubules interspersed with neurofilaments.

The plasmalemma of certain neuroglial cells forms a myelin sheath around some axons, myelinated axons , in both the CNS and the PNS ( Figs. 9.6 and 9.7 ), whereas axons lacking myelin sheaths are called unmyelinated axons ( Fig. 9.8 ). Nerve impulses are conducted much faster along myelinated axons than along unmyelinated axons. In the live individual, the myelin sheath imparts a white, glistening appearance to the axon. It is the presence of myelin that permits the subdivision of the CNS into white matter and gray matter .

Fig. 9.6, Schematic diagram of the process of myelination in the central nervous system. Unlike the Schwann cell of the peripheral nervous system, each oligodendroglion is capable of myelinating several axons.

Fig. 9.7, Diagram of the fine structure of a myelinated nerve fiber and its Schwann cell.

Fig. 9.8, Diagram of the fine structure of an unmyelinated nerve fiber.

In addition to impulse conduction, an important function of the axon is axonal transport of material between the soma and axon terminals. In anterograde transport , the direction of transport is from the cell body to the axon terminal; in retrograde transport , the direction of transport is from the axon terminal to the cell body. Axonal transport is as crucial to trophic relationships within the axon as it is between neurons and muscles or glands. If these relationships are interrupted, the target cells atrophy.

The velocity of axonal transport may be fast, intermediate, or slow. The most rapid transport (up to 400 mm/day) takes place in anterograde transport of organelles, which move more rapidly in the cytosol. In retrograde transport, the fastest speed is about 200 mm/day, with the slowest being only about 0.2 mm/day. Axonal transport speeds between these two extremes are considered intermediate.

  • Anterograde transport is used in the translocation of organelles and vesicles, as well as of macromolecules, such as actin, myosin, and clathrin, and some of the enzymes necessary for neurotransmitter synthesis at the axon terminals.

  • Retrograde transport returns material such as subunits of microtubules and neurofilaments, soluble enzymes, en docytosed substances (e.g., viruses and toxins), and small molecules and proteins destined for degradation, from the axon to the cell body.

  • Axonal transport not only distributes materials for nerve conduction and neurotransmitter synthesis but also serves to provide and ensure general maintenance of the axon cytoskeleton.

Clinical Correlations

Retrograde axonal transport is used by certain viruses (e.g., herpes simplex and rabies virus) to spread from one neuron to the next in a chain of neurons. It is also the method whereby toxins (e.g., tetanus) are transported from the periphery into the CNS.

Since the 1970s, much has been learned about the nature and functioning of the neuron through study of the mechanism of axonal retrograde transport, with the use of the enzyme horseradish peroxidase . In fact, it has become one of the most used techniques in the study of retrograde transport. When this enzyme is injected into the axon terminal, it can be detected later by histochemical techniques that mark its pathway to the cell body. In studying anterograde axonal transport, researchers inject radiolabeled amino acids into the cell body and then later determine the radioactivity at the axon terminals using autoradiography.

Microtubules are important to fast anterograde transport because they exhibit a polarity, with their plus ends directed toward the axon terminal. Tubulin dimers , reaching the axoplasm via anterograde transport, are assembled onto the microtubules at their plus ends and depolymerized at their minus ends. Anterograde transport uses kinesin , a microtubule-associated protein, because one end attaches to a vesicle and the other end interacts in a cyclical fashion with a microtubule, permitting the kinesin to transport the vesicle at a speed of about 3 mm/sec. Retrograde transport uses dynein , another microtubule-associated protein, which is responsible for moving vesicles along the microtubules.

Clinical Correlations

Although neurological tumors account for about 50% of intracranial lesions, tumors of neurons of the CNS are rare. Most intracranial tumors originate from neuroglial cells (e.g., the benign oligodendrogliomas and the fatal malignant astrocytomas ). Tumors that arise from cells of connective tissue associated with nervous tissue (e.g., benign fibroma or malignant sarcoma ) are connective tissue tumors and are not related to the nervous system. Tumors of neurons in the PNS may be extremely malignant (e.g., neuroblastoma in the suprarenal gland, which attacks mostly infants and young children).

Morphological Classification of Neurons ( see Fig. 9.4 )

Neurons are classified morphologically into three major types, according to their shape and the arrangement of their processes.

The major types of neurons are as follows:

  • Bipolar neurons possess two processes emanating from the soma, a single dendrite and a single axon. Bipolar neurons are located in the vestibular and cochlear ganglia and in the olfactory epithelium of the nasal cavity.

  • Unipolar neurons (also known as pseudounipolar neurons ) possess only one process emanating from the cell body, but this process divides into a central branch and a peripheral branch. The central branch enters the CNS and the peripheral branch proceeds to its destination in the body. Both central and peripheral branches resemble an axon and can propagate nerve impulses. The terminal aspect of the peripheral branch arborizes and displays small dendritic ends, indicating its receptor function. Unipolar neurons develop from embryonic bipolar neurons whose processes migrate toward each other during development and fuse, forming a single process that subsequently bifurcates into the central and peripheral processes just described. During impulse transmission, the impulse passes from the end of the peripheral process to the central process without necessarily involving the cell body. Unipolar neurons are located in the dorsal root ganglia of the spinal cord and in the sensory ganglia of the cranial nerves.

  • Multipolar neurons , the most common neuron type, possess various arrangements of several dendrites emanating from the soma, as well as a single axon. Multipolar neurons are present throughout the nervous system, most of which are motoneurons (in older terminology, they were called motor neurons ). Some multipolar neurons are named according to the morphology of their somata (e.g., pyramidal cells) or after the scientist who first described them (e.g., Purkinje cells).

Functional Classification of Neurons

Neurons are classified according to their function into three types: sensory neuron, motoneuron, and interneuron.

  • Sensory neurons ( afferent = toward the CNS ) receive sensory input at their dendritic terminals and conduct impulses to the CNS for processing. Those located in the periphery of the body monitor changes in the external environment; those within the body monitor the internal environment.

  • Motoneurons ( efferent = away from the CNS ) originate in the CNS and conduct their impulses to muscles, glands, and other neurons.

  • Interneurons ( intercalated neurons ), located completely in the CNS, function as interconnectors or integrators that establish networks of neuronal circuits between sensory and motoneurons and other interneurons. With evolution, the number of neurons in the human nervous system has grown enormously, but the greatest increase has involved the interneurons, which are responsible for the complex functioning of the body.

Neuroglial Cells

Neuroglial cells function not only in the physical and metabolic support of neurons but also in regulatory capacities.

Neuroglia not only provide metabolic and mechanical support as well as protection for neurons ( Fig. 9.9 ) but they also have a role in the regulation of neuronal propagation of impulses. It has been estimated that there may be as many as 10 times more neuroglial cells than neurons in the nervous system. Neuroglial cells undergo mitosis, whereas neurons possess a more limited capability of cell division. Although neuroglial cells form gap junctions with other neuroglial cells, they do not react to or propagate nerve impulses, although they assist neurons in the performance of their neural transmission by

  • Keeping a check on synapses

  • Regulating the flow of cerebrospinal fluid ( CSF ) through the substance of the brain

  • Scavenging neurotransmitters released by the axon terminals of neurons

  • Releasing gliotransmitter substances such as adenosine triphosphate (ATP) and glutamic acid into the region of the synapse that may regulate processes that occur there

Fig. 9.9, Diagram of the various types of neuroglial cells (not drawn to scale).

Neuroglial cells that reside exclusively in the CNS include astrocytes, oligodendrocytes, microglia (microglial cells), and ependymal cells. Schwann cells, although located in the PNS, are also considered to be neuroglial cells.

Astrocytes

Astrocytes provide structural and metabolic support to neurons and act as scavengers of ions and neurotransmitters that neurons release into the extracellular space.

Astrocytes are the largest of the neuroglial cells and exist as two distinct types: (1) protoplasmic astrocytes in the gray matter of the CNS and (2) fibrous astrocytes, present mainly in the white matter of the CNS. It is difficult to distinguish the two types of astrocytes in light micrographs, which has led some to suggest that they may be the same cells functioning in different environments. Electron micrographs display distinct cytoplasmic bundles of 8- to 11-nm intermediate filaments composed of glial fibrillar acidic protein , which is unique to astrocytes.

Protoplasmic astrocytes are stellate-shaped cells displaying abundant cytoplasm, a large nucleus, and many short branching processes ( Figs. 9.10 and 9.11 ). The tips of some processes end as pedicels ( vascular feet ) that come into contact with blood vessels. Other astrocytes lie adjacent to blood vessels, with their cell bodies contacting the vessel wall. Still other protoplasmic astrocytes near the brain or surface of the spinal cord exhibit pedicel-tipped processes that contact the pia mater, forming the pia-glial membrane . Protoplasmic astrocytes also function in regulating the flow of CSF through the substance of the brain (see the section on CSF). Some smaller protoplasmic astrocytes located adjacent to neuronal cell bodies are a form of satellite cells.

Fig. 9.10, Electron micrograph of protoplasmic astrocyte (×11,400). Observe the nucleus (N), filaments (F), mitochondria (m), microtubules (t), free ribosomes (r), and granular reticulum (ER). Two lysosomes (L) are also identified in the processes of the neuroglia. Note the irregular cell boundary, indicated by arrowheads . Asterisks indicate processes of other neuroglial cells of the neuropil. (From Peters A, Palay SL, Webster HF. The Fine Structure of the Nervous System . Philadelphia: WB Saunders; 1976.)

Fig. 9.11, This high-magnification photomicrograph of silver-stained human cerebral cortex displays a blood vessel (BV) flanked by numerous stellate-shaped protoplasmic astrocytes (FA) whose several short processes (arrows) approach the vessel wall and end there as pedicels (arrowhead) . (×540)

Fibrous astrocytes possess a euchromatic cytoplasm containing only a few organelles, free ribosomes, and glycogen, and they are surrounded by their own basal lamina ( Fig. 9.12 ). The processes of these cells are long, mostly unbranched, and closely associated with the pia mater and blood vessels but are separated from these structures by their basal lamina.

Fig. 9.12, Light micrograph of a fibrous astrocyte (arrow) in the human cerebellum (×132).

Astrocytes function in removing ions, neurotransmitters, and remnants of neuronal metabolism—such as potassium ions (K + ), glutamate, and γ-aminobutyric acid (GABA)—accumulated in the microenvironment of the neurons, especially at the nodes of Ranvier, where they provide a cover for the axon. These cells also contribute to energy metabolism within the cerebral cortex by releasing glucose from their stored glycogen when induced by the neurotransmitters norepinephrine and vasoactive intestinal peptide (VIP). Astrocytes located at the periphery of the CNS form a continuous layer over the blood vessels and may assist in maintaining the blood–brain barrier . Astrocytes are also recruited to damaged areas of the CNS, where they form cellular scar tissue ( glial scar ).

Oligodendrocytes

Oligodendrocytes function in electrical insulation and in myelin production in the CNS.

Oligodendrocytes, the darkest-staining neuroglial cells, are located in both the gray and the white matter of the CNS. They resemble astrocytes but are smaller and contain fewer processes, with sparse branching. Their dense cytoplasm contains a relatively small nucleus, abundant RER, many free ribosomes, mitochondria, and a conspicuous Golgi complex, as well as microtubules, but mostly in the perinuclear zone and processes ( Fig. 9.13 ). There are two types of oligodendrocytes, interfascicular and satellite.

Fig. 9.13, Electron micrograph of an oligodendrocyte (×2,925). Note the nucleus (N), endoplasmic reticulum (ER), Golgi apparatus (G), and mitochondria (m). Processes of fibrous astrocytes (As) contact the oligodendrocyte.

Interfascicular oligodendrocytes , located in rows beside bundles of axons, manufacture and maintain myelin about the axons in the CNS, serving to insulate them (see Figs. 9.6 and 9.14 ). Unlike Schwann cells of the PNS, oligodendrocytes may have as many as 50 processes, each of which wraps a small region ( internode ) of a single axon with segments of myelin. During active myelin synthesis, interfascicular oligodendrocytes have a very high metabolic rate because they can produce as much as 300 times their weight in myelin on a daily basis. Subsequent to completion of myelinization of all of the internodes under their control, these cells maintain responsibility over the metabolic fate of the myelin that they produced.

Fig. 9.14, Diagrammatic representation of the myelin structure at the nodes of Ranvier of axons in the central nervous system and peripheral nervous system (inset) .

Fig. 9.15, This high-magnification photomicrograph of silver-stained human cerebral cortex displays neuronal cell bodies (Ne) flanked by microglia (Mg) whose several short processes (arrows) radiate in all directions (×540).

Satellite oligodendrocytes are closely applied to cell bodies of large neurons of gray matter. Their function is not understood completely, but they appear to monitor the extracellular fluid around neuronal cell bodies and, according to some investigators, they may act in a reserve capacity. In addition, if the need arises, they may migrate into the white matter to replenish interfascicular oligodendrocytes.

Clinical Correlations

Progressive multifocal leukoencephalopathy is a terminal but rare viral disease caused by a polyoma virus (JC virus) that attacks oligodendrocytes and causes demyelinization of axons, especially in the occipital and parietal lobes of the brain. Although JC virus is present in almost half of the adult population in the United States, it is benign until the patient becomes immunosuppressed and immunodeficient.

Multiple sclerosis (MS) , a relatively common disease affecting more that 2.5 million people throughout the world (approximately 1 million in the United States), is 1.5 to 2 times more common in females than in males. The disease is first diagnosed when the individual is between 15 and 45 years of age. Initially, patients complain about vision problems, difficulties of walking due to balance loss, and tingling sensations in the fingers and toes. These problems are the result of the principal pathological feature of MS: demyelination of axons in the CNS (optic nerve; cerebellum; and white matter of the cerebrum, spinal cord, and cranial and spinal nerves). The characteristic features of MS are episodes of random, multifocal inflammation and edema, followed by periods of remission that may last for several months to decades. Each episode may further jeopardize the patient’s vitality. Any single episode of demyelination may cause deterioration or malignancy of the affected nerves and may lead to death in a matter of months. It was believed that demyelination was due to an immune reaction in which T lymphocytes attacked and destroyed the myelin sheath covering the axons. More recent studies demonstrated that oligodendrogliopathy is the primary cause of MS and the T cell reaction was a secondary response that exacerbated myelin destruction. However, if a drug is administered that either prevents B cells from presenting specific autoantigens to T cells or inhibits T cells from entering the CNS, the degree of oligodendrogliopathy can be diminished and the patient’s MS can be alleviated to a certain extent. Unfortunately, current drugs are unable to do more than decrease the relapses; they cannot cure the disease. Another avenue that is being explored is the effect that intestinal microbial flora has on MS patients. It has been demonstrated that MS patients have much higher levels of Acinetobacter and Akkermansia and much lower levels of Parabacteroides than those of their healthy counterparts. When intestinal bacteria of MS patients were transferred to the intestines of mice that had an MS-like disease, the condition of the mice deteriorated by a significant degree. When the same mice received intestinal flora of healthy patients, they remained healthy. Studies are underway to explore the effects of intestinal microbiomes on MS.

Microglial Cells

Microglia are members of the mononuclear phagocyte system.

Microglial cells , small dark-staining cells that faintly resemble oligodendrocytes, display very little cytoplasm, an oval to triangular nucleus, and irregular short processes with numerous small spines. These cells are phagocytes that originate in the bone marrow and are part of the mononuclear phagocytic cell population whose function is clearing debris and damaged structures in the CNS. Microglial cells also protect the nervous system from viruses, microorganisms, and tumor formation. When activated by the presence of pathogens or damaged neurons in their vicinity, they secrete the cytokine interferon-γ that activates other microglia. These cells also release signaling molecules to recruit T lymphocytes into the CNS and then present epitopes to them, acting as antigen-presenting cells. Microglia also recognize complement-associated proteins C1q and C3 and destroy synapses that present this protein. This is especially true in the developing brain, where neurons form a large number of synapses, many of which are unnecessary and are marked by C1q and/or C3.

Clinical Correlations

  • 1.

    Large populations of microglial cells are present in the brains of patients with Acquired immunodeficiency syndrome (AIDS) and human immunodeficiency virus 1 (HIV-1). Although HIV-1 does not attack neurons, it does attack microglial cells, which then secrete neurotoxic cytokines.

  • 2.

    The complement-associated protein C1q appears to build up at synapses as the individual ages, which results in activation of microglia and subsequent destruction of these synapses. It is possible that, after enough synapses belonging to a specific neuron are destroyed, the neuron itself may undergo degeneration.

Ependymal Cells

Ependymal cells (ependymocytes) , low columnar to cuboidal epithelial cells lining the ventricles of the brain and central canal of the spinal cord, are derived from embryonic neuroepithelium. Their cytoplasm contains abundant mitochondria and bundles of intermediate filaments. In some regions, they possess cilia that facilitate the movement of the CSF.

Where the neural tissue is thin, ependymal cells form an internal limiting membrane lining the ventricle and an external limiting membrane located beneath the pia. Modifications of some of the ependymal cells in the ventricles of the brain participate in the formation of the choroid plexus , which is responsible for secreting and maintaining the chemical composition of the CSF.

Tanycytes , specialized ependymal cells, extend processes into the hypothalamus, where they terminate near blood vessels and neurosecretory cells. It is believed that tanycytes transport CSF to these neurosecretory cells and, possibly under control from the anterior lobe of the pituitary, may respond to changes in hormone levels in the CSF by discharging secretory products into capillaries of the median eminence.

Schwann Cells

Schwann cells form both myelinated and unmyelinated coverings over axons of the PNS.

Unlike other neuroglial cells, Schwann cells are located in the peripheral nervous system, where they envelop axons, forming either myelinated or unmyelinated coverings. Axons of the PNS that have myelin wrapped around them are referred to as myelinated nerves .

Electron microscopy has revealed that myelin is the plasmalemma of individual Schwann cells organized into a sheath that is wrapped several times around a small segment of the axon. Where adjoining Schwann cells form adjoining myelin segments, the axolemma is exposed. These exposed regions are called nodes of Ranvier ( Fig. 9.14 ); the region between adjacent nodes is known as an internode , ranging in length from 200 to 1000 μm. Light microscopy has revealed several cone-shaped, oblique clefts in the myelin sheath of each internodal segment called clefts ( incisures ) of Schmidt-Lanterman , which, viewed with the electron microscope, are Schwann cell cytoplasm trapped within the lamellae of myelin.

Fig. 9.16, Electron micrograph of a myelinated peripheral nerve. Note the internal (i) and external (e) mesaxons, as well as the Schwann cell cytoplasm and nucleus.

A large number of nodes of Ranvier are present along each axon and each node of Ranvier is richly endowed with voltage-gated Na + ion channels . This feature permits an impulse transmission known as saltatory conduction . However, internodes have few, if any, of these channels (see section on generation and conduction of nerve impulses).

The external aspect of Schwann cells is covered by a basal lamina that dips into the nodes of Ranvier. Thus, each Schwann cell is covered by a basal lamina, as is the exposed axon at the node of Ranvier. After nerve injury, the regenerating nerve is guided by the basal lamina to its proper location.

As the membrane spirals around the axon, it produces a series of spiraling, wide, dense lines alternating with narrower, spiraling less dense lines separated from each other by 12 nm. The wider line (3 nm in width) is the major dense line , which represents the fused cytoplasmic surfaces of the Schwann cell plasma membrane. The narrower intraperiod line represents the apposing outer leaflets of the Schwann cell plasma membrane. High-resolution electron microscopy has revealed small gaps within the intraperiod line between spiraled layers of the myelin sheath, called intraperiod gaps . These gaps probably provide access for small molecules to reach the axon. The region of the intraperiod line that is in intimate contact with the axon is known as the internal mesaxon . Its outermost aspect, which is in contact with the body of the Schwann cell, is the external mesaxon (see Figs. 9.7 and 9.16 ).

The process of myelination , whereby the Schwann cell located in the PNS (or oligodendrocyte located in the CNS) concentrically wraps its membrane around the axon to form the myelin sheath, is unclear. It is believed to begin when a Schwann cell envelops an axon and in some fashion wraps its membrane around the axon. The wrapping may continue for more than 50 turns. During this process, the cytoplasm is squeezed back into the body of the Schwann cell, bringing the cytoplasmic surfaces of the membranes in contact with each other, forming the major dense line that spirals through the myelin sheath. A single Schwann cell can myelinate only one internode of a single axon (in the PNS only); oligodendrocytes can myelinate an internode of as many as 50 axons (in the CNS only).

Nerves are not myelinated simultaneously during development. Indeed, the onset and completion of myelination vary considerably in different areas of the nervous system. This variation appears to be correlated with function. For example, motonerves are nearly completely myelinated at birth, whereas sensory roots are not myelinated for several months thereafter. Some CNS nerve tracts and commissural axons are not fully myelinated until several years after birth.

Some axons in the PNS are not wrapped with the many layers of myelin typical of myelinated axons. These unmyelinated axons are surrounded by a single layer of Schwann cell plasma membrane and cytoplasm of the Schwann cell (see Fig. 9.8 ). Although a single Schwann cell can myelinate one axon only, several unmyelinated axons may be enveloped by a single Schwann cell.

Clinical Correlations

Radiation therapy can lead to demyelination of the brain or spinal cord when these structures are in the radiation field during therapy. Toxic agents, such as those used in chemotherapy for cancer, may also lead to demyelination, resulting in neurological problems.

Guillain-Barré syndrome is an immune disorder that produces inflammation and rapid demyelination within the peripheral nerves and the motor nerves arising from the ventral roots. This disease is associated with recent gastrointestinal infection, especially with Campylobacter jejuni . Interestingly, some of the Campylobacter lipopolysaccharide contains ganglioside-like epitopes that resemble some of the lipids present in myelin, which then elicits an autoimmune response resulting in axonal demyelination. A symptom of this disease is muscle weakness in the extremities, reaching a high point within just a few weeks, followed by a more serious condition of demyelination of the nerves serving the diaphragm, making breathing difficult at first and eventually impossible. Early recognition of the condition followed by physical therapy, respiratory therapy, and autoimmune globulin treatments results in possibly complete reversal of the condition.

Generation and Conduction of Nerve Impulses ∗

∗ Although negatively charged proteins within the cytoplasm of the neuron do not cross the cell membrane, they do affect the behavior of the various charged species. However, their role in the generation and conduction of nerve impulses is not described here. The interested reader is referred to textbooks of physiology or neuroscience for an in-depth explanation of these phenomena.

Nerve impulses are generated in the spike trigger zone of the neuron and are conducted along the axon to the axon terminal.

Nerve impulses are electrical signals that are most readily generated at an area of the axon hillock, the spike trigger zone that is exceptionally rich in voltage-gated sodium channels; as the result of membrane depolarization , impulses are conducted along the length of the axon to its axon terminal. Transmission of impulses from the terminals of one neuron to another neuron, a muscle cell, or a gland occurs at synapses (see section on synapses and the transmission of the nerve impulse).

Neurons and other cells are electrically polarized with a resting potential of about −70 mV (this simply means that the cytoplasm adjacent to the neuronal cell membrane is less positive than the extracellular fluid bathing the external aspect of the neuron’s plasmalemma) across the plasma membrane, although in smaller muscle cells and small nerve fibers, this differential may be as low as −40 to −60 mV. This potential arises because of the difference between ion concentrations inside and outside the cell. In mammalian cells, the concentration of potassium (K + ) ions is much higher inside than outside of the cell, whereas the concentration of sodium ions (Na + ) and chloride ions (Cl − ) is much higher outside than inside the cell.

K + ion leak channels in the plasmalemma permit a relatively free flow of K + ions out of a cell down its concentration gradient ( Fig. 9.17 ). Although the K + ion leak channel allows Na + ions to enter the cell, the ratio of potassium to sodium is 100:1 so that many more K + ions leave the cell than Na + ions enter. Thus, a small net positive charge accumulates on the outside of the plasma membrane. Although maintenance of the resting potential depends primarily on K + ion leak channels, Na + -K + ion pumps in the plasma membrane assist by actively pumping Na + ions out of the cell and K + ions into the cell. For every three sodium ions pumped out, two potassium ions enter the cell, making just a slight contribution to the potential difference between the two sides of the membrane.

Fig. 9.17, Schematic diagram of the establishment of the resting potential in a typical neuron. Observe that the potassium ion (K + ) leak channels outnumber the sodium ion (Na + ) and calcium ion (Cl – ) channels. Consequently, more K + can leave the cell than Na + or Cl – can enter. Because there are more positive ions outside than inside of the cell, the outside is more positive than the inside, establishing a potential difference across the membrane. Ion channels and ion pumps not directly responsible for the establishment of resting membrane potential are not shown.

In most cells, the potential across the plasma membrane is generally constant. In neurons and muscle cells, however, the membrane potential can undergo controlled changes, making these cells capable of conducting an electrical signal, as follows:

  • 1.

    Stimulation of a neuron causes opening of voltage-gated Na + ion channels in a small region of the membrane, leading to an influx of Na + ions into the cell at that site ( Fig. 9.18 ). Thus, the overabundance of Na + ions inside the cell causes a reversal of the resting potential (i.e., the cytoplasmic aspect of the plasma membrane becomes positive relative to its extracytoplasmic aspect), and the membrane is said to be depolarized.

    Fig. 9.18, Schematic diagram of the propagation of the action potential in an unmyelinated (A) and myelinated (B) axon (see text).

  • 2.

    Depolarization inactivates those particular Na + ion channels for 1 to 2 msec, a condition known as the refractory period . This is a time during which those particular Na + ion channels are inactive, meaning that they cannot open or close, preventing Na + ions from traversing them. The ability to prevent Na + ions from going through the ion channel is because these channels have two gates, an extracytoplasmic gate ( activation gate ) that opens as a result of the depolarization of the cell membrane and remains open as long as the membrane is depolarized. However, an intracytoplasmic gate ( inactivation gate ) closes within a few ten-thousandths of a second after the opening of the activation gate. Therefore, even though the activation gate remains open, Na + ions are prevented from entering or leaving the cell by the closed inactivation gate.

  • 3.

    During the refractory period, voltage-gated K + ion channels open (note that these are different from the K + ion leak channels described earlier), permitting K + ions to leave the cell and enter the extracellular fluid, thus restoring the resting membrane potential. However, there may be a brief period of hyperpolarization.

  • 4.

    Once the resting potential is restored, the voltage-gated K + ion channels close, and the refractory period is ended with the closing of the activation gate and the opening of the inactivation gate of the voltage-gated Na + ion channel.

The cycle of membrane depolarization, hyperpolarization, and return to the resting membrane potential is called the action potential , an all-or-none response that can occur at rates of 1000 times/sec. The membrane depolarization that occurs with the opening of voltage-gated Na + ion channels at one point on an axon spreads passively for a short distance and triggers the opening of adjacent channels, resulting in the generation of another action potential. In this manner, the wave of depolarization , or impulse , is conducted along the axon. In vivo, an impulse is conducted in only one direction, from the site of initial depolarization to the axon terminal, known as orthodromic spread . The inactivation of the Na + ion channels during the refractory periods prevents retrograde propagation, known as antidromic spread , of the depolarization wave. In an unmyelinated axon , the impulse travels slowly because it involves sodium channels that are adjacent to each other. In myelinated fiber, the impulse travels much faster because it jumps, known as saltatory conduction , from one node of Ranvier to the adjacent node of Ranvier, without having to involve the membrane of the internodes. As stated earlier, the nodes of Ranvier are richly supplied by voltage-gated Na + ion channels , whereas the internodes possess very few, if any, of these channels.

Clinical Correlations

The terminals of the peripheral processes of sensory neurons that are designed to transmit pain sensations possess a very specific type of Na + channels, known as Na V 1.7. When the terminus of one of these nerve fibers is stimulated, the Na V 1.7 channels open, permit the movement of Na + ions into the cell, and thereby initiate the propagation of a nerve impulse. The discovery of these channels provided an explosion of research to find drugs and anesthetics directed specifically toward these channels to provide pain relief and anesthesia without affecting all other sodium channels of the region.

An Alternative Theory of Generation and Conduction of Nerve Impulses

A mechanical, rather than electrical, generation and conduction of nerve impulses has been proposed for a number of years. Known as the soliton theory , it suggests that instead of a wave of electrical depolarization, a shock wave passes along the length of the axon. As this wave progresses, it causes a physical transformation of the lipid bilayer from a fluid phase into a liquid crystalline phase. As this occurs, the axolemma widens and releases heat until the shock wave continues along the axon and the lipid bilayer returns into its fluid phase and reabsorbs the heat that was released. The advantage of the soliton theory is that it provides a better explanation of how anesthetic agents prevent the transmission of pain impulses. This theory suggests that anesthetic agents prevent the fluid phase of the lipid bilayer from entering the liquid crystalline phase.

It must be stressed that the soliton theory has not received even tentative support from most researchers studying the propagation of nerve impulses, even though the membrane phase changes and the heat release and reabsorption aspects of the theory appear to have been verified.

Synapses and the Transmission of the Nerve Impulse

Synapses are the sites of impulse transmission between the presynaptic and postsynaptic cells.

Synapses are the sites where nerve impulses are transmitted from a presynaptic cell (a neuron) to a postsynaptic cell (another neuron, muscle cell, or cell of a gland). Synapses thus permit neurons to communicate with each other and with effector cells (muscles and glands). Impulse transmission at synapses can occur electrically or chemically.

Although electrical synapses are uncommon in mammals, they are present in the brain stem, retina, and cerebral cortex. Electrical synapses are usually represented by gap junctions that permit free movement of small ions from one cell to another, resulting in a flow of current. Impulse transmission is much faster across electrical synapses than across chemical synapses.

Chemical synapses are the most common mode of interneuronal communication. The presynaptic membrane releases one or more neurotransmitters into the synaptic cleft , a small (20- to 30-nm) gap, located between the presynaptic membrane of the first cell and the postsynaptic membrane of the second cell ( Fig. 9.19 ). The neurotransmitter diffuses across the synaptic cleft to gated ion-channel receptors on the postsynaptic membrane. Binding of the neurotransmitter to these receptors initiates the opening of ion channels, which permits the passage of certain ions through the postsynaptic membrane and reverses its membrane potential. Neurotransmitters do not accomplish the reaction events at the postsynaptic membrane; they merely activate the response.

Fig. 9.19, Schematic diagram of the various types of synapses.

When the stimulus at a synapse results in depolarization of the postsynaptic membrane to a threshold value that initiates an action potential, it is called an excitatory postsynaptic potential . A stimulus at the synapse that results in maintaining or increasing the membrane potential, hyperpolarizing it, is called an inhibitory postsynaptic potential .

Various types of synaptic contacts between neurons have been observed, the most common of which are: axodendritic synapse (between an axon and a dendrite), axosomatic synapse (between an axon and a soma), axoaxonic synapse (between two axons), and dendrodendritic synapse (between two dendrites; Figs. 9.19 , 9.20 , and 9.21 ).

Fig. 9.20, Electron micrographs of synapses. The arrow indicates transmission direction. (A) Axodendritic synapse. Presynaptic vesicles are located to the left (×37,600). (B) Axodendritic synapse. Note neurotubules in dendrite (×43,420). (C) Dendrite in cross-section. Note the synapse (×18,800). (D) Axodendritic synapse. Note presynaptic vesicle fusing with the axolemma (×76,000). (E) Axon terminal with clear synaptic vesicles and dense-cored vesicles (×31,000).

Synaptic Morphology

Terminals of axons vary according to the type of synaptic contact. Often, the axon forms a bulbous expansion at its terminal end called a bouton terminal . Other forms of synaptic contacts in axons are derived from swellings along the axon called boutons en passage , where each bouton may serve as a synaptic site.

The cytoplasm at the presynaptic membrane contains mitochondria, a few elements of smooth endoplasmic reticulum (SER), and an abundance of synaptic vesicles assembled around the presynaptic membrane ( Fig. 9.21 ). Synaptic vesicles are spherical structures (40–60 nm in diameter) filled with neurotransmitter substance that usually was manufactured and packaged near the axon terminal. Peptide neurotransmitters, however, are manufactured and packaged in the cell body and are transported to the axon terminal via anterograde transport. Enzymes located in the axoplasm protect neurotransmitters from degradation.

Fig. 9.21, Electron micrograph of an axodendritic synapse. Observe the numerous synaptic vesicles (v) within the axon terminal synapsing with dendrites and the synaptic clefts at these sites (arrows) .

Also located on the cytoplasmic aspect of the presynaptic membrane are cone-shaped densities that project from the membrane into the cytoplasm. They appear to be associated with many of the synaptic vesicles, forming the active site of the synapse. The contents of synaptic vesicles associated with the active site are released at stimulation. Other synaptic vesicles, forming a reserve pool, adhere to actin microfilaments at a slight distance from the active site but migrate there once the active sites are unoccupied. Cell adhesion molecules are known to play an additional role in this process as signaling molecules at both the presynaptic and postsynaptic aspects of the synapse.

Synapsin-I , a small protein that forms a complex with the vesicle surface, probably assists in the clustering of synaptic vesicles that are held in reserve. When synapsin-I is phosphorylated, these synaptic vesicles become free to move to the active site in preparation for release of the neurotransmitter; dephosphorylation of synapsin-I reverses the process.

Synapsin-II and another small protein ( rab3a ) control association of the vesicles with actin microfilaments. Docking of the synaptic vesicles with the presynaptic membrane is under control of two additional synaptic vesicle proteins: synaptotagmin and synaptophysin . When an action potential reaches the presynaptic membrane, it initiates opening of the voltage-gated calcium ion ( Ca 2+ ) channels , permitting Ca 2+ to enter. This Ca 2+ ion influx causes synaptic vesicles, under the influence of SNARE ( SNAP receptor ) proteins (including synaptobrevin , syntaxin , and soluble N -ethylmaleimide–sensitive–fusion protein attachment protein-25 [SNAP-25] ) to fuse with the presynaptic membrane, exocytosing their stored neurotransmitter material into the synaptic cleft.

Excess membrane is recaptured via clathrin-mediated endocytosis . Recycling of synaptic vesicles involves interactions between synaptotagmin and vesicle coat protein AP-2 . The endocytic vesicle fuses with the SER, where new membrane is continuously recycled.

Clinical Correlations

The microorganism Clostridium botulinum produces a protease known as neurotoxin B that specifically cleaves the synaptic vesicle fusion proteins synaptobrevin, syntaxin, and SNAP-25. The toxin is lethal in very small quantities and can be ingested in food from damaged cans or from food that was handled improperly. Neurotoxin B selectively blocks synaptic vesicle fusion with the presynaptic membrane of myoneural junctions, preventing the exocytosis of the neurotransmitter acetylcholine without affecting any other aspect of nerve function. The absence of acetylcholine release results in flaccid paralysis of skeletal muscles. If this condition is not recognized early and antitoxins are not administered, the affected individual will succumb to respiratory failure and death.

The postsynaptic membrane , a thickened portion of the plasma membrane of the postsynaptic cell, contains neurotransmitter receptors . Binding of the neurotransmitter to its receptors initiates depolarization (an excitatory response) or hyperpolarization (an inhibitory response) of the postsynaptic membrane. Neuroglia have been shown to increase synaptogenesis, synaptic efficacy, and action-potential firing.

The relative thicknesses and densities of the presynaptic and postsynaptic membranes, coupled with the width of the synaptic cleft, generally correlate with the nature of the response. A thick postganglionic density and a 30-nm synaptic cleft constitutes an asymmetric synapse , which is usually the site of excitatory responses . A thin postsynaptic density and a 20-nm synaptic cleft constitutes a symmetric synapse , which is usually the site of inhibitory responses .

Neurotransmitters and Neuromodulators

Neurotransmitters and neuromodulators are signaling molecules that are released at the presynaptic membranes and activate receptors on postsynaptic membranes.

Cells of the nervous system communicate mostly by the release of signaling molecules. The released molecules contact receptor molecules protruding from the plasmalemma of the target cell, eliciting a response from the target cell. These signaling molecules were called neurotransmitters . However, such molecules may act on two types of receptors: (1) those directly associated with ion channels and (2) those associated with G proteins or receptor kinases, which activate a second messenger. Therefore, signaling molecules that act as “first messenger systems” (i.e., act on receptors directly associated with ion channels) are now referred to as neurotransmitters . Signaling molecules that invoke the “second messenger system” are referred to as neuromodulators or neurohormones . Because neurotransmitters act directly, the entire process is fast, lasting usually less than 1 msec. Events using neuromodulators are much slower and may last as long as a few minutes.

There are perhaps 100 known neurotransmitters (and neuromodulators) represented by the following four groups:

  • Small-molecule transmitters

  • Neuropeptides

  • Gases

  • Other

Small-molecule transmitters are of three major types:

  • Acetylcholine (the only one in this group that is not an amino acid derivative)

  • Amino acids: glutamate, aspartate, glycine, and GABA

  • Biogenic amines (monoamines)—serotonin; and the three catecholamines—dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline)

Neuropeptides , many of which are neuromodulators, form a large group. They include the following:

  • Opioid peptides: enkephalins and endorphins

  • Gastrointestinal peptides produced by cells of the diffuse neuroendocrine system: substance P, neurotensin, and VIP

  • Hypothalamic-releasing hormones: thyrotropin-releasing hormone and somatostatin

  • Hormones: stored in and released from the neurohypophysis (antidiuretic hormone and oxytocin)

Certain gases act as neuromodulators. They are as follows:

  • Nitric oxide (NO)

  • Carbon monoxide (CO)

The other category of neurotransmitters includes the following:

  • Anandamide, 2-arachidonylglycerol, and virodhamine, all of which bind to cannabinoid receptors

  • Adenosine triphosphate, which binds to both P2X and P2Y receptors

  • Adenosine, which binds to P1 receptors (adenosine receptors)

The most common neurotransmitters are listed in Table 9.1 .

Clinical Correlations

  • 1.

    Huntington disease (HD) is a hereditary condition with an onset at about the third or fourth decade of life that currently afflicts approximately 30,000 people in the United States but genetic testing may show that there is another 200,000 individuals who may inherit the condition. It begins as involuntary jerking movements that progress to severe distortions, dementia, and motor dysfunction. The condition is thought to be related to loss of cells producing GABA , an inhibitory neurotransmitter. Most patients die within 20 years of the initial signs of the disease. The cause of HD appears to be a mutated Huntingtin gene, which interferes with the normal formation of nucleoporins that constitute the nuclear pore complexes, resulting in malfunctioning of transport between the nucleus and the cytoplasm. Although it is not known why, but neurons that are usually affected by this mutation reside in the cerebral cortex, striatum, and basal nuclei (basal ganglia). The malfunctioning of the nucleocytoplasmic transport through the nuclear pore complex eventually causes these cells to die, resulting in Huntington disease and the death of the individual.

  • 2.

    Parkinson disease , a crippling disease related to the absence of dopamine due to degeneration of the dopamine-producing cells in the substantia nigra of the brain, is characterized by muscular rigidity, constant tremor, bradykinesia (slow movement), and, finally, a mask-like face and difficult voluntary movement. Histopathological studies of patients who died of Parkinson disease consistently demonstrated the presence of Lewy bodies, vesicles containing neurofilaments, tau protein, and α-synuclein, in the dopaminergic soma, suggesting that the presence of these bodies are indicative of Parkinson disease. Apparently, the immune system views α-synuclein as an antigen and plasma cells manufacture antibodies against it, causing the death of these dopaminergic cells. The current treatment, although not a cure, consists of the administration of l -dopa (levodopa) and carbidopa, which provides a temporary relief of the motor abnormalities, although the neurons in the affected area continue to die. There are other treatment modalities available, but none that offer a cure.

TABLE 9.1
Properties of the Major Neurotransmitters
Neurotransmitter/Excite or Inhibit Precursor Enzyme Location in Nervous System Miscellaneous
Acetylcholine/excitatory Acetyl CoA and choline Choline acetyltransferase Myoneural junction; autonomic nervous system; striatum Removed by the enzyme acetylcholinesterase; cholinergic neurons degenerate in Alzheimer disease
Glutamate/excitatory Glutamine Glutaminase Most excitatory neurons of the CNS Glutamate-glutamine cycle; excitotoxicity
GABA/inhibitory Glutamate Glutamic acid decarboxylase Mostly local circuit interneurons Decreased GABA synthesis in vitamin B 6 deficiency
Glycine/inhibitory Serine Serine hydroxymethyl-transferase Neurons of the spinal cord Activity blocked by strychnine
Dopamine/excitatory Tyrosine ( L -dopa) Tyrosine hydroxylase Neurons of the substantia nigra, arcuate nucleus, and tegmentum Associated with parkinsonism; inhibition of prolactin release; schizophrenia
Norepinephrine (noradrenalin)/excitatory Tyrosine (dopamine) dopamine β-hydroxylase Postganglionic sympathetic neurons; locus ceruleus Associated with mood and mood disorders (mania, depression, anxiety, and panic)
Epinephrine/excitatory Norepinephrine Phenylethanolamine-N-methyltransferase Rostral medulla Not commonly present in the CNS
Serotonin (5-hydroxy-tryptamine)/excitatory Tryptophan Tryptophan-5-hydroxylase Pineal body; raphe nuclei of midbrain, medulla, pons Associated with sleep modulation; arousal, cognitive behaviors
Substance P/excitatory Amino acids Protein synthesis Dorsal root and trigeminal ganglia (C and A δ fibers) Composed of 11 amino acids; associated with transmission of pain
Somatostatin/inhibitory Amino acids Protein synthesis Amygdala, small ganglion cells, and the hypothalamus Also known as somatotropin release-inhibiting factor
α endorphin/ inhibitory Amino acids Protein synthesis Hypothalamus; nucleus solitarius? Least numerous of the opioid neurotransmitter-containing cells; function in pain suppression
Enkephalins/inhibitory Amino acids Protein synthesis Raphe nucleus; striatum; limbic system; cerebral cortex More numerous than α-endorphin- and enkephalin-containing cells; function in pain suppression
Dynorphin/inhibitory Amino acids Protein synthesis Hypothalamus; amygdala; limbic system More numerous than α-endorphin containing cells; function in pain suppression
ATP/excitatory ADP Oxidative phosphorylation; glycolysis Motoneurons of spinal cord; autonomic ganglia Also co-released with numerous neurotransmitters
Nitric oxide (NO)/inhibitory L-arginine NO synthase Cerebellum; hippocampus; olfactory bulb Smooth muscle relaxant thus strong vasodilator
Acetyl CoA, Acetyl coenzyme A; ADP, adenosine diphosphate; ATP, adenosine triphosphate; CNS, central nervous system; GABA, γ-aminobutyric acid.

Several principles appear to describe the functioning of neurotransmitters. First, a specific neurotransmitter may elicit different actions under varied circumstances. Second, the nature of the postsynaptic receptors determines the effect of a neurotransmitter on postsynaptic cells. Synaptic communication commonly involves multiple neurotransmitters. Additionally, there is mounting evidence for volume transmission as a method of communication between brain cells. According to this concept, chemical and electrical “neurotransmitters,” believed to exist in the extracellular fluid–filled spaces between brain cells, activate groups or fields of cells that contain appropriate receptors rather than activating individual cells. Whereas synaptic communication is fast-acting, volume transmission is thought to be slow and may be related to such conditions as autonomic function, alertness, awareness, changes in brain patterns during sleep, sensitivity to pain, and moods.

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