8 NERVOUS TISSUE

General organization of the nervous system

Anatomically, the nervous system can be divided into (1) the central nervous system (CNS) (the brain, spinal cord, and neural parts of the eye) and (2) the peripheral nervous system (PNS) (peripheral ganglia, nerves, and nerve endings connecting ganglia with the CNS and receptors and effectors of the body). The CNS and PNS are morphologically and physiologically different, and these differences are significant in areas such as neuropharmacology.

The basic cell components of the CNS are neurons and glia. The PNS contains supporting cells called satellite cells and Schwann cells, analogous to the glial cells of the CNS.

We start the study of the nervous tissue by reviewing the highlights of the development of the nervous system.

DEVELOPMENT OF THE NERVOUS SYSTEM

The CNS develops from the primitive ectoderm (Figure 8-1 and Box 8-A). A simple epithelial disk—the neural plate—rapidly rolls into a hollow cylinder—the neural tube. This process is known as neurulation. During this process, a specialized portion of the neural plate—the neural crest—separates from both the neural tube and the overlying ectoderm. In later development, the neural crest forms the neurons of the peripheral ganglia and other components of the PNS. A defect in the closing of the neural tube causes different congenital malformations (see Box 8-B).

Figure 8-1 Early stages of neural tube formation

Box 8-A Three sources of the CNS

• The ectoderm germ cell layer gives rise to three major structures: (1) the surface ectoderm, primarily the epidermis of the skin (including hair, nails, and sebaceous glands), lens and the cornea of the eye, anterior pituitary, and tooth enamel; (2) the neural tube (brain and spinal cord); and (3) the neural crest.

• Cells of the neural crest migrate away from the neural tube and generate components of the peripheral nervous system (Schwann cells and the sympathetic and parasympathetic nervous system), the adrenal medulla, melanocytes of the skin, odontoblasts of the teeth, and neuroglial cells.

Box 8-B Neural tube defects

• A defect in the closing of the neural tube causes different congenital malformations.

Usually, skeletal (skull or vertebral column) defects occur along with malformations of the underlying brain and spinal cord. The latter results from an improper closure of the neural tube during neurulation. Congenital malformations associated with defective neurulation are designated dysraphic (defective fusion) defects.

• Spina bifida is the most common of the spinal cord malformations caused by failure to close the posterior regions of the neural tube. The severity of spina bifida depends on the extent of spinal cord being exposed.

• The most severe example of a neural tube defect of the anterior region of the neural tube is anencephaly, a lethal condition defined by the absence of the brain and the surrounding bone, meninges, muscles, and skin.

• Failure to close the skull and vertebral column is called craniorachischisis.

• Closure of the neural tube in humans requires the expression of specific genes (Pax3, sonic hedgehog, and openbrain). Following closure, the neural tube separates from the surface ectoderm by a process mediated by cell-adhesion molecules N-cadherin and neural cell adhesion molecule (N-CAM). As you recall, the latter is a member of the immunoglobulin superfamily

• The use of periconceptional folic acid supplements prevents ~50%-75% of cases of neural tube defects.

Neural crest cells remain separated from the neural tube and differentiate into (1) the sensory neurons of the dorsal root and cranial nerve ganglia and (2) the sympathetic and parasympathetic motor neurons of the autonomic ganglia.

Some of these cells invade developing visceral organs and form the parasympathetic and enteric ganglia and the chromaffin cells of the adrenal medulla.

The Schwann cells and satellite cells of the dorsal root ganglia also develop from neural crest cells. Schwann cells ensheathe and myelinate the peripheral nerve fibers, and the satellite cells encapsulate the neuronal cell bodies in the dorsal root ganglia.

The early neural tube consists of a pseudostratified columnar epithelium formed by three zones (Figure 8-2): (1) the ventricular zone—the zone where progenitor cells give rise to most cells of the nervous tissue (except microglial cells); (2) the intermediate zone—where neurons migrate toward the cortical plate and where excess neurons are destroyed by apoptosis; and (3) the cortical plate—the future gray matter of the cerebral cortex.

Figure 8-2 Neuronal and glial development

In the ventricular zone, germinal or ventricular cells proliferate rapidly during early development to give rise to ependymoblasts (remaining in the ventricular zone) and glioblasts and postmitotic neurons (migrating to the intermediate zone).

Immature neurons leave the ventricular zone, migrate to the intermediate zone, lose their capacity to undergo cell division, and differentiate into functional neurons. The neuronal migration mechanism and the consequences of abnormal migration are highlighted in Box 8-C.

Box 8-C Neuronal migration

• Neuronal migration involves three highly regulated steps: (1) a growth cone extending away from the cell body; (2) a leading neurite extending from the growth cone and relocation of the centrosome into the neurite; and (3) assembly of microtubules extending from the centrosome toward the nucleus. The nucleus is surrounded by microtubules in a cage-like arrangement and a traction force pulls the nucleus toward the centrosome (nucleokinesis). Actin is also involved in this migration process.

• Mutations affecting neuronal migration have significant effects on the development and function of the CNS. Mental retardation, epilepsy, myopia, and craniofacial abnormalities are observed.

During this differentiation process, a selection process—similar to that in the thymus for T cells (see Chapter 10, Immune-Lymphatic System)—results in either neuronal heterogeneity or death. Neurons that become postmitotic in the intermediate zone reach the outer layers of the cortical plate and continue their differentiation.

Once the production of immature neurons is complete, the germinal or ventricular cells produce glioblasts, which differentiate into astrocytes, oligodendrocytes, and ependymoblasts. Ependymoblasts give rise to ependymal cells, lining the ventricular cavities of the CNS, and choroid epithelial cells, which are components of the choroid plexus.

Later, astrocytes develop vascular end-feet attached to blood vessels of the CNS. Coincident with vascularization is the differentiation of microglia from monocytes. Microglia respond to injury and become active phagocytic cells.

In later development, glioblasts give rise to oligodendrocytes, marking the beginning of myelination in the CNS. In contrast to neurons, glioblasts and derived glial cells retain the ability to undergo cell division.

The number of neurons in the human brain is in the range of 10⁹ to 100⁹. Up to 60% to 70% of these are present in the cerebral cortex. Most neurons are present at birth or shortly thereafter. As the brain continues to grow during the postnatal period, the number and complexity of interneuronal connections increase.

CELL TYPES: NEURONS AND GLIA

Neuron

The functional unit of the nervous system is a highly specialized, excitable cell, the nerve cell or neuron. Neurons usually consist of three principal components (Figures 8-3 and 8-4): (1) soma or cell body, (2) dendrites, and (3) axon.

Figure 8-3 Components of a neuron

Figure 8-4 Components of a neuron

The soma contains the nucleus and its surrounding cytoplasm (also called perikaryon; Greek peri, around; karyon, nucleus).

The dendrites are processes that arise as multiple treelike branches of the soma, forming a dendritic tree collectively. The entire surface of the dendritic branches is covered by small protrusions called dendritic spines. Dendritic spines establish numerous axonal synaptic connections, as we will see later (see Figure 8-7).

Figure 8-5 Types of neurons: Bipolar, pseudounipolar, and multipolar neurons

Figure 8-6 Synaptic transmission

Figure 8-7 Axonal transport

Neurons have a single axon originating from the soma at the axon hillock and ending in a terminal arborization, the telodendron. Each terminal branch of the telodendron has an enlarged ending, the synaptic terminal or synaptic bouton.

Note that although dendrites and axons branch extensively, axons branch at their distal end (the telodendron), whereas dendrites are multiple extensions of the soma or cell body.

The surface membrane of the soma and the dendritic tree are specialized for the reception and integration of information, whereas the axon is specialized for the transmission of information in the form of an action potential or a nerve impulse.

Types of neurons

Different types of neurons can be identified on the basis of the number and length of processes emerging from the soma (Figure 8-5):

According to the number of processes, neurons can be classified as:

1. Multipolar neurons, which display many processes attached to a polygonal-shaped soma. The processes include a single axon and more than one dendrite. Multipolar neurons are the most abundant neurons in the nervous system. Pyramidal cells of the cerebral cortex and Purkinje cells and neurons of the cerebellar cortex are two typical examples.

2. Bipolar neurons have two processes. Bipolar neurons are typical of the visual, auditory, and vestibular systems.

3. Pseudounipolar neurons have only one short process leaving the cell body. They are localized in sensory ganglia of cranial and spinal nerves. Embryonically, pseudounipolar neurons derive from bipolar neuroblasts, and the two neuronal processes fuse during later development (hence the prefix pseudo).

Based on the length of the axon relative to the dendritic tree, multipolar neurons can be subclassified into (1) Golgi type I neurons, when the axon extends beyond the limits of the dendritic tree and (2) Golgi type II neurons, when an axon terminates in the immediate area of the cell body and does not extend beyond the limits of the dendritic tree. Small stellate cells of the cerebral cortex are Golgi type II cells.

Designation of groups of neurons and axons

In the CNS, functionally and structurally related neurons form aggregates called nuclei. An area called the neuropil can be found within a nucleus and between the neuronal cell bodies. The term neuropil designates an area with packed dendrites, axonal branches with abundant synapses, and glial cells.

Clusters of neurons arranged in a layer form a stratum or lamina (cerebral cortex). When neurons form longitudinal groups, these groups are designated columns.

Bundles of axons in the CNS are called tracts, fasciculi (bundles), or lemnisci (for example, the optic tract).

In the PNS, a cluster of neurons forms a ganglion (plural ganglia). A ganglion can be sensory—dorsal root ganglia and trigeminal ganglion—or motor—visceromotor or autonomic ganglia. Axons derived from a ganglion are organized as nerves, rami (singular ramus), or roots.

Synaptic terminals and synapses

The synaptic terminal (Figure 8-6) is specialized for the transmission of a chemical message in response to an action potential. The synapse is the junction between the presynaptic terminal of an axon and a postsynaptic membrane receptor surface, generally a dendrite.

The prefixes pre- and post- refer to the direction of synaptic transmission: (1) Presynaptic refers to the transmitting side (usually axonal). (2) Postsynaptic identifies the receiving side (usually dendritic or somatic, sometimes axonal). The presynaptic and postsynaptic membranes are separated by a space: the synaptic cleft. A dense material coats the inner surface of these membranes: the presynaptic and postsynaptic densities.

Presynaptic terminals contain a large number of membrane-bound vesicles (40 to 100 nm in diameter), the synaptic vesicles. Synaptic vesicles originate in the neuronal soma and are transported by molecular motor proteins along the axon (axonal transport) (Figure 8-7). Each vesicle contains a neurotransmitter. Presynaptic terminals contain mitochondria, components of the smooth endoplasmic reticulum, microtubules, and a few neurofilaments.

Synapses are classified by their location on the postsynaptic neuron (Figure 8-8) as follows:

1. Axospinous synapses are axon terminals facing a dendritic spine.

2. Axodendritic synapses are axon terminals on the shaft of a dendrite.

3. Axosomatic synapses are axon terminals on the soma of a neuron.

4. Axoaxonic synapses are axon terminals ending on axon terminals.

Figure 8-8 Types of synapses

Clinical significance: Axonal transport of rabies virus

The role of the axonal cytoskeleton and motor proteins (kinesin and cytoplasmic dynein; see Figure 8-7) was discussed in the Cytoskeleton section of Chapter 1, Epithelium. We emphasize once more the bidirectional transport of molecules along the axon: kinesin-mediated anterograde axonal transport of neurotransmitters—from the cell body toward the axon terminals, and the cytoplasmic dynein-mediated retrograde axonal transport of growth factors and recycling of axon terminal components—from the axon terminals to the cell body (see Box 8-D).

Box 8-D Neurotransmitters

• Incoming nerve impulses produce focal changes in the resting membrane potential of the neuron that spread along the membrane of dendrites and soma.

Information is conducted along the processes as an electrical excitation (depolarization) generated across the cell membrane.

• As the resting membrane potential diminishes, a threshold level is reached, voltage-gated Ca²⁺ channels open, Ca²⁺ enters the cell, and at that point, the resting potential is reversed: the inside becomes positive with respect to the outside.

• In response to this reversal, the Na⁺ channel closes and remains closed for the next 1 to 2 msec (the refractory period). Depolarization also causes the opening of K⁺ channels through which K⁺ leaves the cell, thus repolarizing the membrane.

• Neuron-to-neuron contacts or synapses are specialized for one-way transfer of excitation. Interneuronal communication occurs at a synaptic junction, the specialized communication site between the terminal of an axon of one neuron and the dendrite of another.

• When an action potential reaches the axon terminal, a chemical messenger or neurotransmitter is released to elicit an appropriate response.

Axonal transport is important in the pathogenesis of neurologic infectious diseases. For example, the rabies virus introduced by the bite of a rabid animal replicates in the muscle tissue from as little as 2 to 16 weeks or longer. After binding to the acetylcholine receptor, the viral particles are mobilized by retrograde axonal transport to the cell body of neurons supplying the affected muscle. The rabies virus continues to replicate within infected neurons and after the shedding of the virions by budding, they are internalized by the terminals of adjacent neurons. Further dissemination of the rabies virus occurs in the CNS. From the CNS, the rabies virus is transported by anterograde axonal transport by the peripheral nerves to the salivary glands. The virus enters the saliva to be transmitted by the bite. Painful spasm of the throat muscles on swallowing accounts for hydrophobia (aversion to swallowing water).

The retrograde axonal transport to the CNS of tetanus toxin—a protease produced by the vegetative spore form of Clostridium tetani bacteria after entering at a wound site—blocks the release of inhibitory mediators at spinal synapses. Spasm contraction of the jaw muscles (known as trismus), exaggerated reflexes, and respiratory failure are characteristic clinical findings.