Neuron

Cells of the central nervous system are divided into two categories, neurons and glial cells. The following entry deals with the characteristics of neurons in the vertebrate central nervous system. Neurons are independent morphological, trophic, and functional entities; they develop from the neural plate of the ectoderm. They differ from glial cells in their ability to generate propagated action potentials (spikes), in the release of neuroactive substances called neurotransmitters, and in their ability to communicate with other cells through specialized membrane junctions called synapses. A long debate in the first half of the twentieth century pitted those who maintained that the brain was a continuous reticulum of fibers against those who proposed that elements of the nervous system were discrete cells (for a historical account see Peters, Palay, and Webster, 1991). The first electron microscopic studies decisively resolved the issue by showing that each neuron is delineated by a continuous plasma membrane and is separated from other cells by a gap. However, like other cells of the body, neurons in some parts of the nervous system are interconnected through continuous cytoplasmic bridges organized into gap junctions that are permeable to ions and small molecules.

Neurons are polarized cells receiving information at certain locations on their plasma membrane and releasing neurotransmitters to other cells, usually from other sites (Kandel and Schwartz, 1985; Peters, Palay, and Webster, 1991; Shepherd, 1990). They emit several processes originating from the cell body or soma. One (occasionally two or three) of the processes is an axon propagating the action potential to the transmitter-releasing nerve terminals. The other processes are called dendrites and are usually shorter and branch less frequently than the axon. The shape and three-dimensional distribution of the processes are characteristic of each category of neuron and reflect their connections with other cells and the neuron's place in the neuronal network. The general arrangement is that information arrives through afferent (i.e., inward-transmitting) synapses on the dendritic processes and the cell body, and is transmitted to other cells through axonal enlargements, also called boutons, present on the axonal arborization. However, significant exceptions to this rule occur in some parts of the brain. Neurons in invertebrates usually have only one process originating from the cell body that gives rise to branches, all of which both receive and give information and are involved in different operations.

The Soma

The soma has a diameter of five to fifty microns and contains the nucleus and the usual cell organelles present in most cells, with great similarity to those present in secretory cells. This is in line with the observation that most neurons secrete proteins and peptides in addition to small transmitter molecules. For example, the rough endoplasmic reticulum (ER), the site of protein synthesis, is often highly developed and is organized into parallel lamellae forming large Nissl bodies. The Golgi apparatus is similarly highly developed and often extends into the proximal dendritic processes, which also contain ER and ribosomes. The axons are usually devoid of ribosomes and, together with the nerve terminals, lack the ability for significant protein synthesis. Thus the neuron is also a polarized biochemical machine where protein and other components synthesized in the cell body are transported through the axon to the nerve terminals.

The transport of molecules and organelles between the processes and the soma is bidirectional and is supported by the cytoskeleton, which also maintains the shape of the processes (Kandel and Schwartz, 1985). The cytoskeleton consists of microtubules (polymers of tubulin dimers, external diameter twenty-five to twenty-eight nanometers); neurofilaments (polymers of cytokeratins, diameter ten nanometers); and microfilaments (polymers of actin, diameter five to seven nanometers).

In addition to rough ER, many neurons are rich in smooth ER that is involved in intracellular Ca₂ + storage and release. Cysternae of the ER are often closely aligned with the plasma membrane of both the soma and dendrites forming subsurface cysternae.

Lysosomes are found in all neurons. Secondary lysosomes accumulate throughout the life of the cell and coalesce into lipofuscin granules showing characteristic distribution for each neuronal type.

The Dendrites

The dendrites are rarely longer than one millimeter and can be as short as ten to fifty microns with a diameter of three to 0.05 microns, tapering toward their tip and decreasing in diameter at branching points. The main difference between them and the axon is that dendrites lack the morphologically distinct initial segment at their origin from the soma. With the exception of peripheral sensory neurons, all neurons have dendrites. They are generally postsynaptic to axon terminals; from scores to tens of thousands of synapses converge on the dendritic tree of a single neuron.

In some parts of the nervous system, most prominently in the retina (amacrine cells), the olfactory bulb, the thalamus, the substantia gelatinosa of the brain stem and spinal cord, and the superior colliculus, dendrites of some classes of cells can be both pre- and postsynaptic. In these cases the dendrite at the presynaptic site contains synaptic vesicles and presynaptic membrane specialization as well as nearby postsynaptic membrane specializations at synapses received by the neuron. Often these combined preand postsynaptic sites are located on protrusions, grapelike clusters or gemmules, isolating the formations from each other on the same cell, and providing a basis for independent action. Synapses between two dendrites can be reciprocal, each partner receiving as well as giving synapses to the other at closely located sites.

Dendrites have various short postsynaptic extrusions, the best-known of them being dendritic spines (see Figure 1). Spines are particularly prominent and numerous on cortical pyramidal and spiny stellate cells, on Purkinje cells, and on the spiny neurons of the neostriatum. Spines frequently contain a specialized organelle, the spine apparatus, consisting of parallel membrane saccules and continuous with the smooth ER of the dendritic shaft. The spine apparatus is thought to be involved in Ca²⁺ sequestration. Spines usually receive excitatory synaptic input and occasionally an additional inhibitory input. Numerous theories have been put forward for the role of spines. Of these, the formation of a biochemical compartment, semi-independent from the dendritic shaft and from other spines, seems the most attractive. The integrative properties of dendrites are determined by 1. their shape; 2. their intrinsic membrane properties, underlined by the presence and distribution of different ion channels ; and 3. the location of synaptic inputs and their relationship to other inputs (for more detail, see Shepherd, 1990).

In addition to receiving and sometimes giving synaptic junctions, dendrites can also be connected to other dendrites and nerve terminals through small cytoplasmic bridges forming gap junctions. Gap junctions are sites of electrotonic transmission because they are permeable to ions and can facilitate the synchronization of neurons.

The Axon

Most neurons have axons; the few exceptions are retinal amacrine cells and granule cells of the olfactory bulb (Shepherd, 1990). Axons usually originate from the soma, rarely from a major dendrite, and begin with the axon hillock. A specialized trilaminar inner coat of the membrane, recognizable with the electron microscope, identifies the axon initial segment, which has the highest density of voltage-sensitive sodium channels. It is thought to be the site of the generation of the propagated-action potential. A similar membrane undercoating is found in the axon at nodes of Ranvier between myelin segments. The other unique feature of the initial segment is the presence of interconnected microtubules organized into fascicles. In some regions of the brain the axon initial segment can receive numerous synapses. Such synapses are provided by the chandelier cell, a specialized inhibitory neuron unique to the cortex, which makes synapses exclusively on the axon initial segment of pyramidal and spiny stellate neurons (see Figure 2). Most axons emit several collaterals along their course, addressing particular brain areas or groups of cells in the same brain area (see Figure 3).

Myelin Sheath

The axons of neurons in the brain can be myelinated for part or for the whole of their course, or can be completely unmyelinated (Peters, Palay, and Webster, 1991). Some types of neurons, such as corticospinal cells and Purkinje cells, always have myelinated axons. The myelin is segmented, and each segment is formed by the plasma membrane of an oligodendroglial cell. Segments are interrupted by nodes of Ranvier, where axon collaterals often originate. The axons may acquire myelin for part of their course as they traverse a particularly heavily myelinated part of the brain. Axons may contain synaptic vesicles at nodes of Ranvier, and they may be presynaptic to neighboring dendrites.

Nerve Terminals

The terminal axon arborizations are characteristic of each cell type. The transmitter-releasing sites are bulbs or varicose enlargements having a diameter usually of 0.5 to three microns; they may have a position on the end of axon branches as boutons terminaux, or may be varicosities along the axon forming boutons en passant (see Figure 1D-G). Many terminal boutons sit on the ends of short stalks branching off from main axon collaterals (see Figure 1D, vertical arrow). Specialized formations of nerve terminals evolved, such as large mossy fiber terminals providing multiple localized input to the same target (see Figure 1E), and climbing fibers providing multiple synapses distributed over the postsynaptic dendritic tree of the same target dendrite or cell. Boutons form synaptic junctions. Boutons are usually only presynaptic to other cells, but terminals of a few cell types, most prominently the primary sensory afterents in the brain stem and spinal cord, may receive synapses and are post-synaptic to inhibitory terminals. One bouton may make synaptic junctions with only one postsynaptic element or may provide input to up to about ten different postsynaptic targets originating from about the same number of individual neurons. In some cases almost every bouton of the same axon establishes synapses with a different cell, providing a large degree of divergence in information transfer. Cortical cells, for example, may make synapses with thousands of other cortical neurons in a given area (see Figure 3).

The boutons contain synaptic vesicles, which are membrane-delineated discrete structures. The morphology of the vesicles is characteristic of cell types and to some degree correlates with the chemistry of their neurotransmitter content. The two most common families of vesicles are the small clear vesicles with a diameter of thirty to fifty nanometers and the large granulated vesicles with a fine electron dense core and a diameter of about eighty to two hundred nano-meters. Boutons are also rich in mitochondria.

The synaptic vesicle-containing varicosities of some neurons do not establish morphologically recognizable synaptic junctions at all of their boutons. This applies in particular to neurons that use monoamines as transmitters.

Analysis of Neuronal Circuits

Connectivity patterns of morphologically identified neurons can be traced via the transport of marker molecules through the processes (Heimer and Zaborszky, 1989). The active transport in the living cell can be exploited by introducing suitable tracers into the neuron that are carried to the dendritic and axonal processes (see Figures 1 and 3). Tracer molecules can be introduced directly into the cell or into the surrounding extracellular space from which the cell can take them up by an active process. It is also possible to label the processes of neurons that have been fixed with chemical agents (see Figure 2). The visualization of processes makes it possible to identify the connections of particular types of neurons in the same area of the brain or among different brain regions. The morphological appearance of neurons reflects their patterns of connections. In many cases synapses from a given source terminate on certain parts of the neuron because the operation that the given input provides is best carried out in that part of the cell (see Figures 1E-G, and 2). Homologous parts of numerous postsynaptic cells in a given area of the brain tend to align with inputs arriving at that part of the cell, and this leads to the development of laminated structures. For example, axons originating from the CA3 region of the hippocampus terminate mainly on the main apical dendrites of pyramidal cells in the CA1 region, and the local recurrent collaterals of pyramidal cells in the CA1 sector address the basal dendritic region of the pyramidal cells (see Figure 1A). The separation of inputs and the minimum amount of axon necessary to achieve addressing is ensured by the alignment of pyramidal cells.

The terminals of some neurons are all localized in the same brain area where the cell body is located. These cells play a role in the local processing of information and are called local circuit neurons (see Figure 2). Other cells connect different brain regions or supply the periphery with their axons; these are called projection neurons. Many projection neurons also have axon collaterals within the same brain area where the cell is located, and thus play both a local circuit and a projection role (see Figure 3). Accurate knowledge of the connectivity, especially in quantitative terms, is a prerequisite of establishing the operations taking place in real neural networks.

See also:NEUROTRANSMITTER SYSTEMS AND MEMORY

Bibliography

Heimer, L., and Zaborszky, L., eds. (1989). Neuroanatomical tracttracing methods, Vol. 2: Recent progress. New York: Plenum Press.

Kandel, E. R., and Schwartz, J. H., eds. (1985). Principles of neural science, 2nd edition, New York: Elsevier.

Kisvarday, Z. F., Martin, K. A. C., Freund, T. F., Magloczky, Z., Whitteridge, D., and Somogyi, P. (1986). Synaptic targets of HRP-filled layer III pyramidal cells in the cat striate cortex. Experimental Brain Research 64, 541-552.

Peters, A., Palay, S. L., and Webster, H. deF., eds. (1991). The fine structure of the nervous system, neurons and their supporting cells, 3rd edition. New York: Oxford University Press.

Shepherd, G. M., ed. (1990). The synaptic organization of the brain, 3rd edition. New York: Oxford University Press.

Somogyi, P., Freund, T. F., Hodgson, A. J., Somogyi, J., Beroukas, D., and Chubb, I. W. (1985). Identified axo-axonic cells are immunoreactive for GABA in the hippocampus and visual cortex of the cat. Brain Research 332, 143-149.

PeterSomogyi