The Axon

Axon is short for axis cylinder. Nerve cells may possess many dendrites but usually have only a single axon, which can be impressively long. Nerve cells projecting between the spinal cord and the brain and from the brain stem and spinal cord to muscles and glands can have axons over 1 m in length. At the other extreme, some small neurons seen in sensory systems have no axons, and these are termed amacrine cells. The main axon may give rise to many collateral branches, which typically branch off at obtuse angles. In some cases, a collateral can ramify within the dendritic field of the parent cell and nearby cells, which is known as a recurrent collateral, and examples of neurons synap-sing upon themselves (autapses) have been described. Unlike dendrites, the diameter ofthe axon usually does not diminish with increasing distance from the cell soma. In a given brain region, neurons are typically classified into projection and intrinsic neurons, according to the trajectory of their axonal ramification. Projection neurons, also called principal, relay, or Golgi type I cells, have long axons and project outside of the region in which the parent cell resides. Intrinsic neurons, also called interneurons or Golgi type II cells, have shorter axons and ramify locally within a brain region. Interneurons tend to have inhibitory influences on their targets and are very important for shaping the spatial and temporal responses of principal neurons.

Axons can arise from either the cell body or primary dendrite, from a coned-shaped region termed the axon hillock. Unlike dendrites, where there is often a gradual changeover in cell constituents from the soma, there is an identifiable transition from soma to axon. The most proximal portion of the axon, which can be recognized in the electron microscope by its characteristic morphology, is referred to as the initial segment. Action potentials arise from the initial segment, which has an extremely high density of Na+ channels. No rough endoplasmic reticulum, ribosomes, or Golgi apparatus extend into the axon much beyond the initial segment. Consistent with the lack of protein synthetic machinery, no protein synthesis is seen in axons. Initial segments can also be recognized in the electron microscope by bundles of microtubules aligned along the axon cylinder and by the presence of a fine, electron-dense fuzz lining the plasma membrane. As with dendrites, the smooth endoplas-mic reticulum extends throughout the axon, where it is sometimes called the axoplasmic reticulum. Microtu-bules are also found throughout the axon, although in larger caliber axons, neurofilaments predominate. The microtubule-associated protein t is concentrated in axons and can be used to identify a neurite as an axon in cell cultures.

Axons are almost totally reliant on the cell body for trophic support, and so axons separated from their somas will obligatorily undergo degeneration. This fact was exploited by early neuroanatomists, particularly in the 1950s and 1960s, for tracing axonal projections. A lesion was placed in an area containing cell bodies and then the brain was stained with silver-based stains specific for degenerating axons. By following the paths of degenerating axons, anatomists could infer the projection patterns of the lesioned neurons. Of course, any axons passing through the lesioned region damaged along with the cell bodies would also degenerate. In the modern anatomical age, degeneration-based methods have been largely replaced by the use of tracers that are injected into the brain, taken up by the cell body, and transported down the axon to their targets.

1. Axonal Transport

Axonal transport, the process by which protein complexes and membranous organelles are transported within axons, has been studied extensively. Axons are capable of bidirectional transport. Transport from the soma to the distal axon is known as anterograde transport, whereas transport from distal regions back to the soma is known as retrograde transport. Axonal transport is an energy-dependent process that involves microtubules and the microtu-bule-based motor proteins, the dyneins and kinesins. Several distinct components have been identified in axonal transport, which differ in their cargoes and the rate of transport. Small membrane-bound organelles such as clear-lumened vesicles and vesiculotubular structures are transported out of the cell soma in the fast component, capable of moving up to 100 mm/day.

Larger membrane-bound structures such as multivesicular bodies carry materials back to the cell body and are also transported by a fast mechanism. Mitochondria move independently of the anterograde and retrograde flows, and the axoplasmic reticulum is stationary relative to fast transport. Cytoskeletal and cytoplasmic proteins are transported much more slowly, on the order of 1-10 mm/day.

2. The Action Potential

Axons are able to transmit signals to their targets by the conduction of action potentials along their length. The action potential involves a sudden membrane depolarization followed by a rapid reversal. The ionic basis of the action potential was elucidated by Alan Hodgkin and Andrew Huxley in the 1940s and 1950s in pioneering studies using the giant axon of the squid. The main currents involved in generating the action potential are carried by Na + and K + ions. Na + is much more concentrated in the extracellular environment, whereas K + tends to be more concentrated inside the axon. The plasma membrane of axons contains ion channels permeable to Na + and K + . These ion channels are known as voltage-gated channels in that the internal potential of the cell will determine whether the channel is open or closed. If the potential reaches a certain threshold value, the ion channel will undergo a conformational change that causes it to either open or close. The normal resting potential of a neuron is on the order ofโ€”60 to โ€”70 mV, which is largely the result of a high concentration of K + ions inside the axon.

An action potential is initiated in the axon hillock when the synaptic signals received by the dendrites and soma are sufficient to raise the intracellular potential to the threshold potential of โ€” 55 mV. When this potential is reached, the Na + channels present in the axon initial segment will open. Na + ions rush into the cell, causing rapid reversal of the membrane potential from โ€”90 to +40 mV. When the membrane potential reaches +40 mV, the Na+ channels close and the voltage-gated K+ channels open. K+ ions move out of the axon, thereby repolarizing the membrane. As a result of this coordination of Na+ and K+ channels, the action potential is circumscribed in time and restricted in space to a local patch of membrane. However, some current spreads passively down the axon, driving the membrane potential toward threshold in an adjacent patch of membrane and the process is repeated. In this way, the action potential is propagated down the axon in an anterograde direction without a loss of amplitude. The action potential is prevented from traveling back toward the soma due to factors that make the preceding patch of membrane refractory to stimulation. Following the cessation of the action potential, Na + /K+ ATPases in the membrane remove Na+ from the interior of the cell and uptake K+ from the extracellular space, restoring the proper ionic balance. The speed of conduction in different axons varies tremendously from slow conduction (~0.5m/sec) to very fast (80-120m/sec). The speed of conduction of a given axon is directly proportional to the axon diameter and the density of ion channels in the membrane. Another major determinant of the speed of axon conduction is the presence or absence of the myelin sheath.

3. The Myelin Sheath

Fast-conducting axons in the vertebrate nervous system are wrapped in a thick, fatty coating called myelin, which is formed by glial cells. Myelin in the peripheral nervous system is formed by a type of glial cell known as the Schwann cell, whereas in the central nervous system, myelin is formed by the class of glia known as oligodendroglia or oligodendrocytes. Under the electron microscope, myelin appears as a series of concentric layers enveloping the axon (Fig. 8). These layers are actually the membrane of a single myelinat-ing glial cell spiraled around the axon cylinder with the cytoplasm of the glial cell squeezed out. The dark staining is due to the fixation of the nerve cell with the heavy metal osmium tetroxide, which reacts primarily

Figure 8 Electron micrograph of a myelinated nerve fiber in a rat peripheral nerve. (Left) Cross section of a myelinated axon showing the characteristic dense staining of the myelin sheath. Part of the cytoplasm of the Schwann cell forming the myelin sheath is also visible. (Right) Higher magnification view of the myelin sheath showing the concentric layers of the myelin sheath formed by the plasma membrane of the Schwann cell spiraling around the axon with the cytoplasm squeezed out. Some of the Schwann cell cytoplasm is visible around the outer layer of the myelin sheath. Microtubules (mt) and neurofilaments (nf) cut in cross section are clearly visible.

Figure 8 Electron micrograph of a myelinated nerve fiber in a rat peripheral nerve. (Left) Cross section of a myelinated axon showing the characteristic dense staining of the myelin sheath. Part of the cytoplasm of the Schwann cell forming the myelin sheath is also visible. (Right) Higher magnification view of the myelin sheath showing the concentric layers of the myelin sheath formed by the plasma membrane of the Schwann cell spiraling around the axon with the cytoplasm squeezed out. Some of the Schwann cell cytoplasm is visible around the outer layer of the myelin sheath. Microtubules (mt) and neurofilaments (nf) cut in cross section are clearly visible.

with lipids and adds significantly more electron-scattering stain to these sites. In unstained tissue, the presence of myelin is what gives bundles of axons their macroscopic white, shiny appearance.

The presence of the myelin sheath tremendously increases the speed and efficiency of nerve conduction by improving the capacitive and resistive properties of the axon cable. The myelin sheath of these insulated axons is not continuous but is interrupted at regular intervals, 1-2 mm apart. The interruptions occur where the ensheathment of one glial cell ends and another begins (Fig. 9). The gaps in the myelin sheath were first described in the 1870s by the French neuroanatomist Louis-Antoine Ranvier, who also described myelin, and have been named nodes of Ranvier in his honor. Nodes of Ranvier have high concentrations ofNa+ andK+ channels in the plasma membrane. The myelin sheath serves as an insulator to the axon, preventing the leakage of ions across the membrane in the internodal regions. Action potentials are generated only at the node, rather than continuously down the length of the axon. This form of axonal conduction is called saltatory conduction because the action potential jumps from node to node. Myelina-tion is usually observed in axons > 1 mm in diameter. Smaller axons in the peripheral nervous system are still ensheathed by Schwann cells, but no myelin is formed. In the central nervous system, small axons usually have no glial covering. The importance of the myelin sheath for normal nerve function is underscored by the devastating effects of demyelinating diseases, such as multiple sclerosis, which result in significant neurological impairments.

E. The Synapse

The term synapse (Gr: ''fasten together'') was first coined by the physiologist Charles Sherrington in the late nineteenth century. Synapses are specialized cellular junctions that are the site of intercellular communication between neurons and their targets. Two types of synapses are distinguished, chemical and electrical. Electrical synapses are also known as gap junctions and are formed by proteins called connexins, which provide a low-resistance conduit between cells where ions and other small molecules can pass directly from cell to cell. Transmission through electrical synapses is very rapid and can provide a mechanism for synchronizing the firing of groups of connected neurons. Electrical synapses are more common between neurons in invertebrates but are found in vertebrates as well. Gap junctions are not unique to nerve cells but are also formed between glial cells and are found in other types of tissue. The most common form and best-studied synapse in the vertebrate nervous system is the chemical synapse, where signals are passed from one cell to the next through the agency of chemical neurotransmitters (Fig. 10). The neuro-transmitter is released from small vesicles contained in the axon terminals of one cell (designated the pre-synaptic cell), diffuses across the extracellular space, and interacts with receptor proteins located in the postsynaptic cell. The postsynaptic cell is most commonly a neuron, but it can also be a muscle, gland, or organ. In fact, most of what is known about synaptic transmission is derived from studies of the neuromus-cular junction, the synapse between motor neurons and the skeletal musculature, because this synapse is large and relatively accessible compared to synapses in the central nervous system.

Chemical synapses provide polarized, point-to-point zones of intercellular communication. Anatomically, synapses are difficult to identify conclusively at the light microscopic level without some sort of special stain, although Ramon y Cajal correctly identified the expansions at the axon terminal closely apposed to the dendrites and somata of other nerve cells as the point of intercellular communication. The anatomical correlate of the synapse was described definitively by Sanford Palay, George Palade, and others with the advent of biological electron microscopy starting in the 1950s (Fig. 10). Synapses can occur at the terminal end of axons, in which case they are called synaptic terminals or synaptic boutons, or they can occur along the length of the axon at local swellings. This type of synapse is very common in the mammalian nervous system and is called an en passant synapse. In myelinated axons, the en passant synapse occurs at the nodes of Ranvier. In the case of the terminal boutons, axons lose their myelin sheath prior to the terminal expansion.

The synapse and its associated specializations are most clearly visualized under the electron microscope (Fig. 10). Presynaptically, the synapse is characterized by the presence of a concentration of clear vesicles,

Brain Electron Microscopy Images

Figure 10 Electron micrograph of an asymmetrical synaptic contact onto a dendritic spine (S) in the rat cerebellum. The characteristic features of a synaptic contact are clearly visible, including the concentration of vesicles in the presynaptic axon terminal (AT), the widening of the extracellular cleft at the site of contact, and the presence of a prominent postsynaptic density (arrowheads). This synaptic complex is surrounded by an astrocytic process.

Figure 10 Electron micrograph of an asymmetrical synaptic contact onto a dendritic spine (S) in the rat cerebellum. The characteristic features of a synaptic contact are clearly visible, including the concentration of vesicles in the presynaptic axon terminal (AT), the widening of the extracellular cleft at the site of contact, and the presence of a prominent postsynaptic density (arrowheads). This synaptic complex is surrounded by an astrocytic process.

referred to as synaptic vesicles, ~40nm in diameter. These vesicles contain neurotransmitter molecules, which are released upon activation (see later discussion). Vesicles are clustered around presynaptic membrane specializations, consisting of a series of regularly spaced, electron-dense projections termed the active zone, believed to aid in the docking of vesicles for the release of neurotransmitter. More elaborate synaptic specializations can be seen in some synapses, such as the synaptic body of the vestibular hair cell and the ribbon class synapses found in several cell types. These specializations are thought to serve as a mechanism for conveying vesicles to docking sites. Other elements present in the presynaptic terminal include dense-core vesicles, mitochondria, microtubules, neurofilaments, and smooth endoplasmic reticulum.

The synaptic cleft, the intercellular gap across which the neurotransmitter diffuses, is also distinct. It tends to be wider than the average nonsynaptic distance between cells, on the order of ~ 20-25 nm, and contains electron-dense material. Fine filaments have been described spanning the cleft. Numerous cell adhesion molecules such as the NCAMs (neural cell adhesion molecules) and cadherins are found at the synapse, which serve to anchor the pre- and post-synaptic membranes. The adherence at the synapse is very strong and has been exploited in biochemical studies where intact synaptic complexes, or synapto-somes, can be recovered using cell fractionation techniques.

On the postsynaptic side, the major feature is the presence of a postsynaptic specialization consisting of electron-dense, filamentous material apposed to the postsynaptic membrane directly across the cleft from the active zone (Fig. 10). The electron dense material in the postsynaptic cell is called the postsynaptic density. In some types of synapses, especially those occurring in dendritic spines, the postsynaptic density is quite prominent, giving an asymmetrical appearance to the synapse. These synapses are often referred to as asymmetrical synapses and tend to be associated with excitatory synaptic transmission. Other synapses have much less prominent postsynaptic densities and are usually referred to as symmetrical synapses. Often, these synapses are associated with inhibitory synaptic transmission. These distinctions are not absolute and many synapses of intermediate morphology have been described. Asymmetrical and symmetrical synapses were first described by Edward Gray in the 1950s and are sometimes referred to as Gray's type I and type II synapses, respectively.

Much progress has been made to elucidate the composition of the postsynaptic membrane and density. In addition to neurotransmitter receptors, the postsynaptic membrane also contains proteins called cadherins as well as other adhesion molecules responsible for the tight adherence of pre- and postsynaptic membranes. Cytoskeletal proteins such as actin, tubulin, and fodrin are present in high abundance. Proteins involved in the anchoring of neurotransmitter receptors and ion channels to the cytoskeleton have also been identified. These proteins, also known as PDZ domain containing proteins, serve both to anchor neurotransmitter receptors and ion channels in the postsynaptic membrane and to link neurotransmitter receptors to downstream signaling proteins forming large macromolecular complexes. Other multifunctional signal transduction proteins such as CaM kinase II, DARP32, and protein kinase C may also be present in the postsynaptic density. Thus, the postsynaptic density serves to concentrate and organize signal transduction machinery at the synapse.

Synaptic complexes do not usually occur in isolation in the vertebrate nervous system but are closely associated with glial cells. In the central nervous system, the processes of astrocytes envelop or partially surround the presynaptic terminal and sometimes wrap around both the pre- and postsynaptic elements (Fig. 10). Astrocytes are the most numerous type of glial cell in the central nervous system. The extent of glial investiture of synapses varies across brain regions and even from synapse to synapse in a given brain region. Astrocytic processes are known to be able to take up certain neurotransmitters like glutamate from the extracellular environment and also to regulate the extracellular concentration of K+ ions. Studies have suggested that glial cells are important for regulating synaptic transmission at glutamatergic synapses and for protecting against neurotoxic concentrations of glutamate in the extracellular space.

1. Synaptic Transmission

Chemical neurotransmission is a carefully regulated process. Synaptic transmission at the chemical synapse involves multiple steps and thus is slower than transmission through electrical synapses, but it provides the advantage of directionality and amplification of signal transmission. The major steps involved in the most rapid form of chemical synaptic transmission can be summarized as follows. Action potentials invade the synaptic terminal and open voltage-sensitive calcium channels present in the plasma membrane. Calcium triggers a series of molecular interactions ultimately causing vesicles in the vicinity of the vesicle docking area or active zone to fuse with the presynaptic membrane and release their contents into the synaptic cleft. This process is very fast, occurring on a sub-millisecond time scale. The neurotransmitter diffuses across the synaptic cleft and interacts with neuro-transmitter receptors anchored to the postsynaptic membrane by cytoskeletal proteins in the postsynaptic density. Excess neurotransmitter either is broken down by enzymes located in the cleft, diffuses away from the synaptic site, or is taken up by the presynaptic cell through the action of transporter molecules present in the presynaptic membrane or surrounding glial cells. Lipids and specific proteins contained in the synaptic vesicle are then recycled from the plasma membrane using a clathrin-mediated mechanism, and in most systems the recycled vesicles are refilled with neurotransmitter and otherwise readied for another release cycle. A large number of proteins involved in vesicle docking, transmitter uptake and release, signal transduction, and vesicle recycling have been identified. Unraveling of the molecular players in synaptic transmission is critical not only because synaptic transmission is fundamental to the functioning of the nervous system but also because many toxins and neuroactive drugs target proteins involved in this process.

The binding of a neurotransmitter to its receptor can result in several postsynaptic events occuring simultaneously. In some cases, the neurotransmitter receptor is an ion channel that allows Na+ or Ca2+ into the cell (called ionotropic receptors). Ionotropic responses tend to be fast, occurring in the millisecond range. In other cases, the neurotransmitter activates a second messenger system like cyclic AMP or phosphoinositol breakdown (metabotropic receptors). The actions initiated via these metabotropic receptors are much slower than ionotropic response, occurring over seconds or even minutes. The result of neurotransmission can be either excitatory or inhibitory. Excitatory neurotransmission drives the postsynaptic neuron closer to firing an action potential, whereas negative neurotransmission drives the neuron farther from firing an action potential. Excitatory responses tend to involve intracellular increases of Na+ or K+ ions, resulting in membrane depolarization, whereas inhibitory responses usually involve increases of Cl_ ions, resulting in hyperpolarization. Beyond the voltage changes observed in the postsynaptic cell, a host of other signal transduction cascades are activated, usually in response to a rise in intracellular calcium. Calcium can activate various enzyme complexes such as protein kinases and proteases. Signals can be propagated to the nucleus to activate gene transcription. Several immediate early genes such as c-fos are turned on as a result of synaptic activation.

A variety of small molecules are now known to act as neurotransmitters. The prototypical fast excitatory neurotransmitter in the vertebrate nervous system is the amino acid glutamate, whereas the most common inhibitory neurotransmitter is g-aminobutyric acid, usually referred to as GABA. Although these molecules are referred to as excitatory or inhibitory, in fact a neurotransmitter is neither excitatory or inhibitory, because its action depends upon the type of receptor present and the state of the postsynaptic cell. Other well-characterized neurotransmitters include acetyl-choline, glycine, and the biogenic amine transmitters serotonin, dopamine, and norepinephrine. These molecules have all been identified as neurotransmitters on the basis of well-established criteria, such as their presence in presynaptic terminals and their interaction with specific receptors. Many other neuroactive substances are also released from the synapse along with recognized neurotransmitters, such as the fatty acid arachadonic acid, ATP, and even gases such as nitric oxide. Many of these act as neuromodulators, in that they modify the response of the cell to a neurotrans-mitter. These substances are not necessarily contained in synaptic vesicles but may be released directly from the terminal.

The brain contains a large number of neuroactive peptides, short chains of amino acids, such as the enkephalins, substance P, and neurotensin, which also function as neurotransmitters and neuromodulators. Neuropeptides are contained in vesicles in the terminal, but in the large dense-core vesicles and not the small clear vesicles seen in Fig. 10. Unlike other neurotransmitters that are synthesized locally in the axon terminal via specific enzymes, peptides are synthesized in the cell body, packaged in the vesicles via the Golgi apparatus, and transmitted to the terminal. Peptides interact with specific receptors that activate second messenger molecules and, thus, tend to be associated with slow synaptic transmission. They are often colocalized and coreleased from the synaptic terminal with one of the better characterized transmitters. However, exocitosis from dense-core vesicles does not occur at the presynaptic active zone but can occur anywhere in the nerve terminal or along the axon. Release from dense-core vesicles requires a higher concentration of Ca2+ than does release from clear vesicles and generally occurs when the nerve is firing at high frequency. Thus, although both fast and slow neurotransmitters may be contained in the same nerve terminal, they may be released under different circumstances.

2. Synaptic Arrangements and Integration

The most common site of synaptic contact on a neuron is on the dendrites or dendritic spines. These types of synapses are referred to as axodendritic or axospinous. In cells that possess dendritic spines, the vast majority of synapses occur onto the spine heads, whereas few synapses are observed onto the dendritic shaft. In fact, it has been estimated that over 90% of excitatory synaptic inputs in the brain occur onto dendritic spines. Synapses also occur onto the cell soma and axon initial segment. In general, those synapses that occur onto the cell soma, initial segment, and proximal dendrites tend to be inhibitory in nature. For example, in the cerebellum, hippocampus, and cortex, an inhibitory interneuron termed the basket cell forms pericellular baskets surrounding the somata of projection neurons and establishing numerous inhibitory synaptic contacts. Inputs more distally and onto dendritic spines tend to be excitatory. In some areas of the brain, most notably the olfactory bulb, dendrites are capable of forming synapses onto other dendrites. These special arrangements are called dendrodendritic synapses because a dendrite is serving as both the pre-and the postsynaptic element. Reciprocal synapses, where each dendrite serves as both the pre- and the postsynaptic cell, have also been described.

Whether a neuron will initiate an action potential in response to synaptic activation will depend upon the spatial and temporal integration of excitatory and inhibitory activation over the whole cell. Excitatory and inhibitory influences are summed over the entire dendritic tree and cell body and integrated in the soma. If threshold is reached, an action potential is initiated in the axon hillock, the spike initiation zone. Previously, it was thought that ionic spread from dendrites to soma occurred exclusively through passive diffusion. However, several ion channels have been localized in the dendritic plasmalemma and some dendrites are known to possess the ability to fire action potentials.

Individual neurons vary widely in the number of synapses they receive, averaging approximately 1000 per neuron. Generally, if a neuron receives a large number of synapses, each synapse is relatively weak and the simultaneous activity of multiple synapses is necessary to excite the postsynaptic cell. An example of a cell that receives large numbers of weak synapses is the Purkinje cell found in the cerebellum, which receives up to 150,000 synapses onto its dendritic spines from the cerebellar granule cell. Each granule cell exerts relatively little influence on the Purkinje cell, and so multiple granule cells must be activated to cause the Purkinje cell to fire an action potential. In contrast, other types of synapses are very powerful, such as the synapse formed at the neuromuscular junction where every action potential in the nerve fiber results in a corresponding action potential in the muscle cell. Individual neurons can receive a mixture of strong and weak synapses. The strength of an individual synapse will be determined principally by the amount and duration of transmitter released upon stimulation and also its location on the postsynaptic cell. Those synapses occurring closer to the cell soma tend to exert a stronger postsynaptic effect than those occurring more distally.

The large number of synapses received by an individual nerve cell indicates that there can be a tremendous convergence of information at the cellular level. Divergence of information also occurs, because a single axon can synapse with many cells either through the en passant type along the course of the axon or by ramification of synaptic terminals. In several regions of the brain, a specialized arrangement called a glomerulus (L: "small ball'') is seen. The glomerulus consists of a very large presynaptic bouton, which contacts multiple postsynaptic dendrites. In the cere-bellar mossy fiber glomerulus, the presynaptic terminal can measure 10-20 mm in length and can contact up to 50 dendrites. Glomerular arrangements are also seen in the thalamus, olfactory bulb, and several other brain regions.

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