Overview of the Microstructure of the Nervous System

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Chapter 2 Overview of the Microstructure of the Nervous System

The nervous system has two major divisions, the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the brain and spinal cord and contains the majority of neuronal cell bodies. The PNS includes all nervous tissue outside the CNS and is subdivided into the cranial and spinal nerves, autonomic nervous system (ANS) (including the enteric nervous system (ENS) of the gut wall) and special senses (taste, olfaction, vision, hearing and balance). It is composed mainly of the axons of sensory and motor neurones that pass between the CNS and the body. However, the ENS contains as many intrinsic neurones in its ganglia as the entire spinal cord, is not connected directly to the CNS, and may be considered separately as a third division of the nervous system.

The CNS is derived from the neural tube (Ch. 3). The cell bodies of neurones are often grouped together in areas termed nuclei, or they may form more extensive layers or masses of cells collectively called grey matter. Neuronal dendrites and synaptic activity are mostly confined to areas of grey matter, and they form part of its meshwork of neuronal and glial processes that is collectively termed the neuropil (Fig. 2.1). Their axons pass into bundles of nerve fibres that tend to be grouped separately to form tracts. In the spinal cord, cerebellum, cerebral cortices and some other areas, concentrations of tracts constitute the white matter, so called because the axons are often ensheathed in myelin, which is white when fresh (see Figs. 8.16, 8.19).

Fig. 2.1 Neuronal somata, dendrites and axons in the CNS neuropil; their cytoskeleton has been stained using a gold method. The toluidine blue counterstaining reveals the nuclei of surrounding glial cells.

(By permission from Young, B., Heath, J.W., 2000. Wheater’s Functional Histology. Churchill Livingstone, Edinburgh.)

The PNS is composed of the axons of motor neurones situated inside the CNS and the cell bodies of sensory neurones (grouped together as ganglia) and their processes. Sensory cells in dorsal root ganglia give off both centrally and peripherally directed processes; there are no synapses on their cell bodies. Ganglionic neurones of the ANS receive synaptic contacts from various sources. Neuronal cell bodies in peripheral ganglia are all derived embryologically from cells that migrate from the neural crest (Ch. 3).

When the neural tube is formed during prenatal development, its walls thicken greatly but do not completely obliterate the cavity within. The latter remains in the spinal cord as the narrow central canal, and in the brain it becomes greatly expanded to form a series of interconnected cavities called the ventricular system. In the fore- and hindbrains, parts of the neural tube roof do not generate nerve cells but become thin, folded sheets of secretory tissue that are invaded by blood vessels and are called the choroid plexuses. The plexuses secrete cerebrospinal fluid (CSF), which fills the ventricles and subarachnoid spaces (Ch. 4). and penetrates the intercellular spaces of the brain and spinal cord to create their interstitial fluid. The CNS has a rich blood supply, which is essential to sustain its high metabolic rate. The blood–brain barrier places considerable restrictions on the substances that can diffuse from the blood stream into the nervous tissue.

Neurones encode information, conduct it over considerable distances and then transmit it to other neurones or to various non-neural cells. The movement of this information within the nervous system depends on the rapid conduction of transient electrical impulses along neuronal plasma membranes. Transmission to other cells is mediated by secretion of neurotransmitters at special junctions either with other neurones (synapses) or with cells outside the nervous system, such as muscle cells (neuromuscular junctions), gland cells and adipose tissue, and this causes changes in their behaviour.

The nervous system contains large populations of non-neuronal cells, neuroglia or glia that, although not electrically active in the same way, are responsible for creating and maintaining an appropriate environment in which neurones can operate efficiently. In the CNS, glia outnumber neurones by 10 to 50 times and consist of microglia and macroglia. Macroglia are further subdivided into three main types: oligodendrocytes, astrocytes and ependymal cells. The principal glial cell of the PNS is the Schwann cell. Satellite cells surround each neuronal soma in ganglia.

Neurones

Most of the neurones in the CNS are either clustered into nuclei, columns or layers or dispersed within grey matter. Neurones of the PNS are confined to ganglia. Irrespective of location, neurones share many general features, which are discussed here in the context of central neurones. Special characteristics of ganglionic neurones and their adjacent tissues are discussed later in this chapter.

Neurones exhibit great variability in size (cell bodies range from 5 to 100 µm diameter) and shape. Their surface areas are extensive because most neurones display numerous narrow, branched cell processes. They usually have a rounded or polygonal cell body (perikaryon or soma). This is a central mass of cytoplasm that encloses a nucleus and gives off long, branched extensions, with which most intercellular contacts are made. Typically, one of these processes, the axon, is much longer than the others, the dendrites (Fig. 2.2). Dendrites conduct electrical impulses toward a soma, whereas axons conduct impulses away from it.

Fig. 2.2 Typical neurone (here, a motor neurone) showing the soma; part of the dendritic tree, with dendritic spines and synaptic contacts; and an axon myelinated by oligodendrocytes and (in the PNS) Schwann cells and ending at a neuromuscular junction.

Neurones can be classified according to the number and arrangement of their processes. Multipolar neurones (Fig. 2.3; see also Fig. 16.9) are common; they have an extensive dendritic tree, which arises either from a single primary dendrite or directly from the soma, and a single axon. Bipolar neurones, which typify neurones of the special sensory systems (e.g., retina), have only a single dendrite that emerges from the soma opposite the axonal pole. Unipolar neurones that transmit general sensation (e.g., dorsal root ganglion neurones) have a single short process that bifurcates into peripheral and central processes, an arrangement that arises by the fusion of the proximal axonal and dendritic processes of a bipolar neurone during development.

Fig. 2.3 Section through the cerebral cortex (mouse) stained by the Golgi method, which demonstrates only a small proportion of the total neuronal population.

(Specimen prepared by Martin Sadler, Division of Anatomy and Cell Biology, GKT School of Medicine, London.)

Neurones are postmitotic cells and, with few exceptions, are not replaced when lost.

Soma

The plasma membrane of the soma is unmyelinated and contacted by inhibitory and excitatory axosomatic synapses; very occasionally, somasomatic and dendrosomatic contacts may be made. The non-synaptic surface is covered by either astrocytic or satellite oligodendrocyte processes.

The cytoplasm of a typical soma (see Fig. 2.2) is rich in rough and smooth endoplasmic reticulum and free polyribosomes, which reveals a high level of protein synthetic activity. Free polyribosomes often congregate in large groups associated with the rough endoplasmic reticulum. These aggregates of RNA-rich structures are visible by light microscopy as basophilic Nissl (chromatin) bodies or granules (Fig. 2.4). They are more obvious in large, highly active cells such as spinal motor neurones, which contain large stacks of rough endoplasmic reticulum and polyribosome aggregates. Maintenance and turnover of cytoplasmic and membranous components are necessary in all cells; the huge total volume of cytoplasm within the soma and processes of many neurones requires a considerable commitment of protein synthetic machinery. Neurones synthesize other proteins (e.g., enzyme systems) involved in the production of neurotransmitters and in the reception and transduction of incoming stimuli. Various transmembrane channel proteins and enzymes are located at the surfaces of neurones, where they are associated with ion transport. The apparatus for protein synthesis (including RNA and ribosomes) occupies the soma and dendrites but is usually absent from axons.

Fig. 2.4 Large multipolar neuronal perikarya in the magnocellular part of the feline red nucleus, showing prominent Nissl granules, bases of dendrites and axon hillocks. The nuclei are euchromatic and vesicular, with prominent nucleoli. The small nuclei scattered in the surrounding neuropil are characteristic of the various categories of neuroglial cell.

(Photograph by Kevin Fitzpatrick on behalf of GKT School of Medicine, London.)

The nucleus is characteristically large, round and euchromatic, with one or more prominent nucleoli, as is typical of all cells engaged in substantial levels of protein synthesis. The cytoplasm contains many mitochondria and moderate numbers of lysosomes. Golgi complexes are typically seen close to the nucleus, near the bases of the main dendrites and opposite the axon hillock.

The neuronal cytoskeleton is a prominent feature of its cytoplasm, and it gives shape, strength and rigidity to the dendrites and axons. Neurofilaments (the intermediate filaments of neurones) and microtubules are abundant; they occur in the soma and extend along dendrites and axons, in proportions that vary with the type of neurone and cell process. Bundles of neurofilaments constitute neurofibrils, which can be seen by light microscopy in silver stained sections. Neurofilaments are heteropolymers of proteins assembled from three polypeptide subunits: NF-L (68 kDa), NF-M (160 kDa) and NF-H (200 kDa). NF-M and NF-H have long C-terminal domains that project as side arms from the assembled neurofilament and bind to neighbouring filaments. They can be heavily phosphorylated, particularly in the highly stable neurofilaments of mature axons, and are thought to give axons their tensile strength. Some axons are almost filled by neurofilaments. Dendrites usually have more microtubules than axons.

Microtubules are important in axonal transport. Centrioles persist in mature postmitotic neurones, where they are concerned with the generation of microtubules rather than cell division. Centrioles are associated with cilia on the surfaces of developing neuroblasts. Their significance, other than at some sensory endings (e.g., the olfactory mucosa), is not known.

Pigment granules appear in certain regions (e.g., neurones of the substantia nigra contain neuromelanin), probably a waste product of catecholamine synthesis. In the locus coeruleus a similar pigment, rich in copper, gives neurones a bluish colour. Some neurones are unusually rich in certain metals, which may form a component of enzyme systems, such as zinc in the hippocampus and iron in the oculomotor nucleus. Ageing neurones, especially in spinal ganglia, accumulate granules of lipofuscin (senility pigment). They represent residual bodies, which are lysosomes packed with partially degraded lipoprotein material (corpora amylacea).

Dendrites

Dendrites are highly branched, usually short processes that project from the soma (see Fig. 2.2). The branching patterns of many dendritic arrays are probably established by random adhesive interactions between dendritic growth cones and afferent axons that occur during development. There is an overproduction of dendrites in early development, which is pruned in response to functional demand as the individual matures and information is processed through the dendritic tree. There is evidence that dendritic trees may be plastic structures throughout adult life, expanding and contracting as the traffic of synaptic activity varies through afferent axodendritic contacts. Groups of neurones with similar functions have a similar stereotypical tree structure (Fig. 2.5), suggesting that the branching patterns of dendrites are important determinants of the integration of afferent inputs that converge on the tree.

Fig. 2.5 Purkinje neurone from the cerebellum of a rat stained by the Golgi–Cox method, showing the extensive two-dimensional array of dendrites.

(Courtesy of Martin Sadler and M. Berry, Division of Anatomy and Cell Biology, GKT School of Medicine, London.)

Dendrites differ from axons in many respects. They represent the afferent rather than the efferent system of the neurone, and they receive both excitatory and inhibitory axodendritic contacts. They may also make dendrodendritic and dendrosomatic connections (see Fig. 2.8), some of which are reciprocal. Synapses occur either on small projections called dendritic spines or on the smooth dendritic surface. Dendrites contain ribosomes, smooth endoplasmic reticulum, microtubules, neurofilaments, actin filaments and Golgi complexes. The neurofilament proteins of dendrites are poorly phosphorylated. Dendrite microtubules express the microtubule-associated protein (MAP-2) almost exclusively, in comparison with axons.

Dendritic spine shapes range from simple protrusions to structures with a slender stalk and expanded distal end. Most spines are no more than 2 µm long and have one or more terminal expansions, but they can also be short and stubby, branched or bulbous. Free ribosomes and polyribosomes are concentrated at the base of the spine. Ribosomal accumulations near synaptic sites provide a mechanism for activity-dependent synaptic plasticity through the local regulation of protein synthesis.

Axons

The axon originates either from the soma or from the proximal segment of a dendrite, at a specialized region called the axon hillock (see Fig. 2.2), which is free of Nissl granules. Action potentials are initiated here. The axonal plasma membrane (axolemma) is undercoated at the hillock by a concentration of cytoskeletal molecules, including spectrin and actin fibrils, which are thought to be important in anchoring numerous voltage-sensitive channels to the membrane. The axon hillock is unmyelinated and often participates in inhibitory axo-axonal synapses. This region of the axon is unique because it contains ribosomal aggregates immediately below the postsynaptic membrane.

When present, myelin begins at the distal end of the axon hillock. Myelin thickness and internodal segment lengths are positively correlated with axon diameter. In the PNS unmyelinated axons are embedded in Schwann cell cytoplasm; in the CNS they lie free in the neuropil. Nodes of Ranvier are specialized constricted regions of myelin-free axolemma where action potentials are generated and where an axon may branch. The density of sodium channels in the axolemma is highest at the nodes of Ranvier and very low along internodal membranes. In contrast, sodium channels are spread more evenly within the axolemma of unmyelinated axons. Fast potassium channels are also present in the paranodal regions of myelinated axons. Fine processes of glial cytoplasm (astrocyte in the CNS, Schwann cell in the PNS) surround the nodal axolemma. The terminals of an axon are unmyelinated. They expand into presynaptic boutons, which may form connections with axons, dendrites, neuronal somata or, in the periphery, muscle fibres, glands and lymphoid tissue. They may themselves be contacted by other axons, forming axo-axonal presynaptic inhibitory circuits. Further details of neuronal microcircuitry are given in Kandel and Schwartz (2000).

Axons contain microtubules, neurofilaments, mitochondria, membrane vesicles, cisternae and lysosomes; they do not usually contain ribosomes or Golgi complexes, except at the axon hillock. However, ribosomes are found in the neurosecretory fibres of hypothalamo-hypophysial neurones, which contain the mRNA of neuropeptides. Organelles are differentially distributed along axons; for instance, there is a greater density of mitochondria and membrane vesicles in the axon hillock, at nodes and in presynaptic endings. Axonal microtubules are interconnected by cross-linking microtubule-associated proteins (MAPs), of which tau is the most abundant. Microtubules have an intrinsic polarity: in axons, all microtubules are uniformly oriented with their rapidly growing ends directed away from the soma and toward the axon terminal. Neurofilament proteins ranging from high to low molecular weights are highly phosphorylated in mature axons, whereas growing and regenerating axons express a calmodulin-binding membrane-associated phosphoprotein and growth-associated protein-43 (GAP-43), as well as poorly phosphorylated neurofilaments.

Axons respond differently to injury, depending on whether the damage occurs in the CNS or PNS. The glial microenvironment of a damaged central axon does not facilitate regrowth, and reconnection with original synaptic targets does not normally occur. In the PNS the glial microenvironment is capable of facilitating axonal regrowth; however, the functional outcome of clinical repair of a large mixed peripheral nerve, especially if the injury occurs some distance from the target organ or produces a long defect in the damaged nerve, is frequently unsatisfactory.

Axoplasmic Flow

Neuronal organelles and cytoplasm are in continual motion. Bidirectional streaming of vesicles along axons results in a net transport of materials from the soma to the terminals, with more limited movement in the opposite direction. Two major types of transport occur—one slow, and one relatively fast. Slow axonal transport is a bulk flow of axoplasm only in the anterograde direction, carrying cytoskeletal proteins and soluble, non-membrane-bound proteins at a rate of 0.1 to 3 mm a day. In contrast, fast axonal transport carries vesicular material at approximately 200 mm a day in the retrograde direction and 40 mm a day anterogradely.

Rapid flow depends on microtubules. Vesicles with side projections line up along microtubules and are transported along them by their side arms. Two microtubule-based motor proteins with ATPase activity are involved in fast transport. Kinesin family proteins are responsible for the fast component of anterograde transport, and cytoplasmic dynein is responsible for retrograde transport. Fast anterograde transport carries vesicles, including synaptic vesicles containing neurotransmitters, from the soma to the axon terminals. Retrograde axonal transport accounts for the flow of mitochondria, endosomes and lysosomal autophagic vacuoles from the axon terminals into the soma. Retrograde transport mediates the movement of neurotrophic viruses (e.g., herpes zoster, rabies, polio) from peripheral terminals and their subsequent concentration in the neuronal soma.

Synapses

Transmission of impulses across specialized junctions (synapses) between two neurones is largely chemical. It depends on the release of neurotransmitters from the presynaptic side; this causes a change in the electrical state of the postsynaptic neuronal membrane, resulting in either its depolarization or its hyperpolarization.

The patterns of axonal termination vary considerably. A single axon may synapse with one neurone, such as climbing fibres ending on cerebellar Purkinje neurones; more often, it synapses with many, such as cerebellar parallel fibres, which provide an extreme example of this phenomenon. In synaptic glomeruli (e.g., in the olfactory bulb) and synaptic cartridges, groups of synapses between two or more neurones form interactive units encapsulated by neuroglia (Fig. 2.6).

Fig. 2.6 Arrangement of complex synaptic units. A, Synaptic glomerulus with excitatory (+) and inhibitory (–) synapses grouped around a central dendritic terminal expansion. The directions of transmission are shown by the arrows. B, Synaptic cartridge with a group of synapses surrounding a dendritic segment. Each complex unit is enclosed within a glial capsule (green).

Electrical synapses (direct communication via gap junctions) are rare in the human CNS and are confined largely to groups of neurones with tightly coupled activity, such as the inspiratory centre in the medulla. They are not discussed further here.

Classification of Chemical Synapses

Chemical synapses have an asymmetric structural organization (Figs 2.7, 2.8), in keeping with the unidirectional nature of their transmission. Typical chemical synapses share a number of important features. They all display an area of presynaptic membrane apposed to a corresponding postsynaptic membrane; the two are separated by a narrow (20 to 30 nm) gap, the synaptic cleft. Synaptic vesicles containing neurotransmitters lie on the presynaptic side, clustered near an area of dense material on the cytoplasmic aspect of the presynaptic membrane. A corresponding region of submembrane density is present on the postsynaptic side. Together these define the active zone, the area of the synapse where neurotransmission takes place.

Fig. 2.7 Electron micrographs demonstrating various types of synapses. A, Pale cross-section of a dendrite on which two synaptic boutons end. The upper bouton contains round vesicles, and the lower bouton contains flattened vesicles of the small type. A number of pre- and postsynaptic thickenings mark the specialized zones of contact. B, Type I synapse containing both small, round, clear vesicles and large, dense-core vesicles of the neurosecretory type. C, Large terminal bouton of an optic nerve afferent fibre, making contact with a number of postsynaptic processes, in the dorsal lateral geniculate nucleus of a rat. One of the postsynaptic processes (*) also receives a synaptic contact from a bouton containing flattened vesicles (right). D, Reciprocal synapses between two neuronal processes in the olfactory bulb.

(A and C, Courtesy of A.R. Lieberman, Department of Anatomy, University College, London.)

Fig. 2.8 Structural arrangements of different types of synaptic contact. A, The gap junction (B) and the desmosome (E) have no synaptic significance. Excitatory synaptic boutons are shown (C and G), containing small, spherical, translucent vesicles. Also depicted are a bouton with dense-core, catecholamine-containing vesicles (D); an inhibitory synapse containing small flattened vesicles (F); a reciprocal synaptic structure between two dendritic profiles, inhibitory toward the dendrite (A) and excitatory in the opposite direction (H); an inhibitory synapse containing large flattened vesicles (I); two serial synapses—one (J) excitatory to the dendrite and one (K) inhibitory to J; and a neurosecretory ending (L) adjacent to a vascular channel (M), surrounded by a fenestrated endothelium. All the boutons in this diagram are of the terminal type except for G, which is a bouton de passage. B, Axosomatic and axoinitial segment synapses. FS, symmetric synapses with flattened vesicles; RA, asymmetric synapses with rounded vesicles. C, Ribbon synapse: triad at the base of a retinal rod.

Chemical synapses can be classified according to a number of different parameters, including the neuronal regions forming the synapse, their ultrastructural characteristics, the chemical nature of their neurotransmitters and their effects on the electrical state of the postsynaptic neurone. The classification described here is limited to associations between neurones. Neuromuscular junctions share many (although not all) of these parameters and are often referred to as peripheral synapses. They are described separately in Chapter 22.

Synapses can occur between almost any surface regions of the participating neurones. The most common type occurs between an axon and either a dendrite or a soma, when the axon is expanded as a small bulb or bouton (see Figs. 2.7, 2.8). This may be a terminal of an axonal branch (terminal bouton) or one of a row of bead-like endings, with the axon making contact at several points and often with more than one neurone (bouton de passage). Boutons may synapse with dendrites, including dendritic spines or the flat surface of a dendritic shaft; a soma, usually on its flat surface, but occasionally on spines; the axon hillock and the terminal boutons of other axons.

The connection is classified according to the direction of transmission, with the incoming terminal region named first. Most common are axodendritic synapses, although axosomatic connections are frequent. All other possible combinations are found, but they are less common: axoaxonic, dendroaxonic, dendrodendritic, somatodendritic and somatosomatic. Axodendritic and axosomatic synapses occur in all regions of the CNS and in autonomic ganglia, including those of the ENS. The other types appear to be restricted to regions of complex interaction between larger sensory neurones and microneurones, such as in the thalamus.

Ultrastructurally, synaptic vesicles may be internally clear or dense and of different sizes (loosely categorized as small or large) and shape (round, flat or pleomorphic, i.e., irregularly shaped). The submembranous densities may be thicker on the postsynaptic than on the presynaptic side (asymmetric synapses) or equivalent in thickness (symmetric synapses). Synaptic ribbons are found at sites of neurotransmission in the retina and inner ear. They have a distinctive morphology, in that the synaptic vesicles are grouped around a ribbon- or rod-like density oriented perpendicular to the cell membrane (see Fig. 2.8).

Synaptic boutons make obvious close contacts with postsynaptic structures, but many other terminals lack specialized contact zones. Areas of transmitter release occur in the varicosities of unmyelinated axons, where the effects are sometimes diffuse (e.g., the aminergic pathways of the basal ganglia and in autonomic fibres in the periphery). In some instances, such axons may ramify widely throughout extensive areas of the brain and affect the behaviour of very large populations of neurones (e.g., the diffuse cholinergic innervation of the cerebral cortices). Pathological degeneration of these pathways can therefore cause widespread disturbances in neural function.

Neurones express a variety of neurotransmitters, either as one class of neurotransmitter per cell or, more often, as several. Good correlations exist between some types of transmitters and specialized structural features of synapses. In general, asymmetric synapses with relatively small spherical vesicles are associated with acetylcholine (ACh), glutamate, serotonin (5-hydroxytryptamine, or 5-HT) and some amines; those with dense-core vesicles include many peptidergic synapses and other amines (e.g., noradrenaline (norepinephrine), adrenaline (epinephrine), dopamine). Symmetric synapses with flattened or pleomorphic vesicles have been shown to contain either γ-aminobutyric acid (GABA) or glycine.

The neurosecretory endings found in various parts of the brain and in neuroendocrine glands have many features in common with presynaptic boutons. They all contain peptides or glycoproteins within dense-core vesicles of characteristic size and appearance. These are often ellipsoidal or irregular in shape and relatively large; for example, oxytocin and vasopressin vesicles in the neurohypophysis may be up to 200 nm across.

Synapses may cause depolarization or hyperpolarization of the postsynaptic membrane, depending on the neurotransmitter released and the classes of receptor molecule in the postsynaptic membrane. Depolarization of the postsynaptic membrane results in excitation of the postsynaptic neurone, whereas hyperpolarization has the effect of transiently inhibiting electrical activity. Subtle variations in these responses may also occur at synapses where mixtures of neuromediators are present and their effects are integrated.