neuroscience Neuroscience is the scientific study of the nervous system (the brain, spinal cord, and peripheral nervous system), its functions and disorders. It is a multidisciplinary science that combines physiology, anatomy, molecular biology, deve ...

and

anatomy Anatomy () is the branch of biology concerned with the study of the structure of organisms and their parts. Anatomy is a branch of natural science that deals with the structural organization of living things. It is an old science, having its ...

, nodes of Ranvier ( ), also known as myelin-sheath gaps, occur along a

myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...

ated

axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...

where the

axolemma In neuroscience, the axolemma (, and 'axo-' from axon) is the cell membrane of an axon, the branch of a neuron through which signals (action potentials) are transmitted. The axolemma is a three-layered, bilipid membrane. Under standard electron ...

is exposed to the

extracellular space Extracellular space refers to the part of a multicellular organism outside the cells, usually taken to be outside the plasma membranes, and occupied by fluid. This is distinguished from intracellular space, which is inside the cells. The compositi ...

. Nodes of Ranvier are uninsulated and highly enriched in

ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ...

s, allowing them to participate in the exchange of

ion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conv ...

s required to regenerate the

action potential An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...

. Nerve conduction in myelinated axons is referred to as

saltatory conduction In neuroscience, saltatory conduction () is the propagation of action potentials along myelinated axons from one node of Ranvier to the next node, increasing the conduction velocity of action potentials. The uninsulated nodes of Ranvier are th ...

() due to the manner in which the action potential seems to "jump" from one node to the next along the axon. This results in faster conduction of the action potential.

Overview

Many vertebrate axons are surrounded by a myelin sheath, allowing rapid and efficient saltatory ("jumping") propagation of action potentials. The contacts between neurons and

glial cells Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form mye ...

display a very high level of spatial and temporal organization in myelinated fibers. The myelinating

oligodendrocytes Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...

in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all pa ...

(CNS), and Schwann cells in the peripheral nervous system (PNS) - are wrapped around the axon, leaving the axolemma relatively uncovered at the regularly spaced nodes of Ranvier. The internodal glial membranes are fused to form compact

, whereas the cytoplasm-filled paranodal loops of myelinating cells are spirally wrapped around the axon at both sides of the nodes. This organization demands a tight developmental control and the formation of a variety of specialized zones of contact between different areas of the myelinating cell membrane. Each node of Ranvier is flanked by paranodal regions where helicoidally wrapped glial loops are attached to the axonal membrane by a septate-like junction. The segment between nodes of Ranvier is termed as the internode, and its outermost part that is in contact with paranodes is referred to as the juxtaparanodal region. The nodes are encapsulated by

microvilli Microvilli (singular: microvillus) are microscopic cellular membrane protrusions that increase the surface area for diffusion and minimize any increase in volume, and are involved in a wide variety of functions, including absorption, secretion, ce ...

stemming from the outer aspect of the

Schwann cell Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ens ...

membrane in the PNS, or by perinodal extensions from

astrocytes Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...

in the CNS.

Structure

The internodes are the

segments and the gaps between are referred to as nodes. The size and the spacing of the internodes vary with the fiber diameter in a curvilinear relationship that is optimized for maximal conduction velocity. The size of the nodes span from 1–2 μm whereas the internodes can be up to (and occasionally even greater than)1.5 millimetres long, depending on the axon diameter and fiber type. The structure of the node and the flanking paranodal regions are distinct from the internodes under the compact

sheath, but are very similar in CNS and PNS. The axon is exposed to the extra-cellular environment at the node and is constricted in its diameter. The decreased axon size reflects a higher packing density of neurofilaments in this region, which are less heavily phosphorylated and are transported more slowly. Vesicles and other organelles are also increased at the nodes, which suggest that there is a bottleneck of axonal transport in both directions as well as local axonal-glial signaling. When a longitudinal section is made through a myelinating

at the node, three distinctive segments are represented: the stereotypic internode, the paranodal region, and the node itself. In the internodal region, the

has an outer collar of cytoplasm, a compact

sheath, and inner collar of cytoplasm, and the axolemma. At the paranodal regions, the paranodal cytoplasm loops contact thickenings of the axolemma to form septate –like junctions. In the node alone, the axolemma is contacted by several Schwann microvilli and contains a dense cytoskeletal undercoating.

Differences in the central and peripheral nervous systems

Although freeze fracture studies have revealed that the nodal axolemma in both the CNS and PNS is enriched in intra-membranous particles (IMPs) compared to the internode, there are some structural differences reflecting their cellular constituents. In the PNS, specialized microvilli project from the outer collar of Schwann cells and come very close to nodal axolemma of large fibers. The projections of the Schwann cells are perpendicular to the node and are radiating from the central axons. However, in the CNS, one or more of the astrocytic processes come in close vicinity of the nodes. Researchers declare that these processes stem from multi-functional astrocytes, as opposed to from a population of astrocytes dedicated to contacting the node. On the other hand, in the PNS, the basal lamina that surrounds the Schwann cells is continuous across the node.

Composition

The nodes of Ranvier Na+/Ca2+ exchangers and high density of voltage-gated Na+ channels that generate action potentials. A sodium channel consists of a pore-forming α subunit and two accessory β subunits, which anchor the channel to extra-cellular and intra-cellular components. The nodes of Ranvier in the central and peripheral nervous systems mostly consist of αNaV1.6 and β1 subunits. The extra-cellular region of β subunits can associate with itself and other proteins, such as tenascin R and the cell-adhesion molecules neurofascin and contactin. Contactin is also present at nodes in the CNS and interaction with this molecule enhances the surface expression of Na+ channels.

Ankyrin Ankyrins are a family of proteins that mediate the attachment of integral membrane proteins to the spectrin-actin based membrane cytoskeleton. Ankyrins have binding sites for the beta subunit of spectrin and at least 12 families of integral mem ...

has been found to be bounded to βIV spectrin, a spectrin isoform enriched at nodes of Ranvier and axon initial segments. The PNS nodes are surrounded by

microvilli, which contain ERMs and EBP50 that may provide a connection to actin microfilaments. Several extracellular matrix proteins are enriched at nodes of Ranvier, including tenascin-R, Bral-1, and proteoglycan NG2, as well as phosphacan and

versican Versican is a large extracellular matrix proteoglycan that is present in a variety of human tissues. It is encoded by the ''VCAN'' gene. Versican is a large chondroitin sulfate proteoglycan with an apparent molecular mass of more than 1000kDa. ...

V2. At CNS nodes, the axonal proteins also include contactin; however,

microvilli are replaced by

astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...

perinodal extensions.

Molecular organization

The molecular organization of the nodes corresponds to their specialized function in impulse propagation. The level of sodium channels in the node versus the internode suggests that the number IMPs corresponds to sodium channels. Potassium channels are essentially absent in the nodal axolemma, whereas they are highly concentrated in the paranodal axolemma and Schwann cell membranes at the node. The exact function of potassium channels have not quite been revealed, but it is known that they may contribute to the rapid repolarization of the action potentials or play a vital role in buffering the potassium ions at the nodes. This highly asymmetric distribution of voltage-gated sodium and potassium channels is in striking contrast to their diffuse distribution in unmyelinated fibers. The filamentous network subjacent to the nodal membrane contains cytoskeletal proteins called

spectrin Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane in eukaryotic cells. Spectrin forms pentagonal or hexagonal arrangements, forming a scaffold and playing an important role in maintenance of plasma memb ...

and

ankyrin Ankyrins are a family of proteins that mediate the attachment of integral membrane proteins to the spectrin-actin based membrane cytoskeleton. Ankyrins have binding sites for the beta subunit of spectrin and at least 12 families of integral mem ...

. The high density of

at the nodes may be functionally significant because several of the proteins that are populated at the nodes share the ability to bind to

with extremely high affinity. All of these proteins, including

, are enriched in the initial segment of axons which suggests a functional relationship. Now the relationship of these molecular components to the clustering of sodium channels at the nodes is still not known. Although some cell-adhesion molecules have been reported to be present at the nodes inconsistently; however, a variety of other molecules are known to be highly populated at the glial membranes of the paranodal regions where they contribute to its organization and structural integrity.

Development

Myelination of nerve fibers

The complex changes that the

undergoes during the process of myelination of peripheral nerve fibers have been observed and studied by many. The initial envelopment of the axon occurs without interruption along the entire extent of the

. This process is sequenced by the in-folding of the

surface so that a double membrane of the opposing faces of the in-folded

surface is formed. This membrane stretches and spirally wraps itself over and over as the in-folding of the

surface continues. As a result, the increase in the thickness of the extension of the

sheath in its cross-sectional diameter is easily ascertained. It is also evident that each of the consecutive turns of the spiral increases in size along the length of the axon as the number of turns increase. However, it is not clear whether or not the increase in length of the

sheath can be accounted solely by the increase in length of axon covered by each successive turn of the spiral, as previously explained. At the junction of two Schwann cells along an axon, the directions of the lamellar overhang of the

endings are of opposite sense. This junction, adjacent of the Schwann cells, constitutes the region designated as the node of Ranvier.

Early stages

Researchers prove that in the developing CNS, Nav1.2 is initially expressed at all forming nodes of Ranvier. Upon maturation, nodal Nav1.3 is down-regulated and replaced by Nav1.6. Naz1.2 is also expressed during PNS node formation, which suggests that the switching of Nav-channel subtypes is a general phenomenon in the CNS and PNS. In this same investigation, it was shown that Nav1.6 and Nav1.2 colocalize at many nodes of Ranvier during early myelination. This also led to the suggestion that early clusters of Nav1.2 and Nav1.6 channels are destined to later become nodes of Ranvier. Neurofascin is also reported to be one of the first proteins to accumulate at newly forming nodes of Ranvier. They are also found to provide the nucleation site for attachment of ankyrin G, Nav channels, and other proteins. The recent identification of the

microvilli protein gliomedin as the likely binding partner of axonal neurofascin brings forward substantial evidence for the importance of this protein in recruiting Nav channels to the nodes of Ranvier. Furthermore, ''Lambert et al.'' and ''Eshed et al.'' also indicates that neurofascin accumulates before Nav channels and is likely to have crucial roles in the earliest events associated with node of Ranvier formation. Thus, multiple mechanisms may exist and work synergistically to facilitate clustering of Nav channels at nodes of Ranvier.

Nodal formation

The first event appears to be the accumulation of cell adhesion molecules such as NF186 or NrCAM. The intra-cellular regions of these cell-adhesion molecules interact with ankyrin G, which serves as an anchor for sodium channels. At the same time, the periaxonal extension of the glial cell wraps around the axon, giving rise to the paranodal regions. This movement along the axon contributes significantly to the overall formation of the nodes of Ranvier by permitting heminodes formed at the edges of neighboring glial cells to fuse into complete nodes. Septate-like junctions form at the paranodes with the enrichment of NF155 in glial paranodal loops. Immediately following the early differentiation of the nodal and paranodal regions, potassium channels, Caspr2 and TAG1 accumulate in the juxta-paranodal regions. This accumulation coincides directly with the formation of compact

. In mature nodal regions, interactions with the intracellular proteins appear vital for the stability of all nodal regions. In the CNS,

do not possess microvilli, but appear capable to initiate the clustering of some axonal proteins through secreted factors. The combined effects of such factors with the subsequent movements generated by the wrapping of

oligodendrocyte Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...

periaxonal extension could account for the organization of CNS nodes of Ranvier.

Function

Action potential

is a spike of both positive and negative ionic discharge that travels along the membrane of a cell. The creation and conduction of action potentials represents a fundamental means of communication in the nervous system. Action potentials represent rapid reversals in voltage across the plasma membrane of axons. These rapid reversals are mediated by voltage-gated ion channels found in the

plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

. The action potential travels from one location in the cell to another, but ion flow across the membrane occurs only at the nodes of Ranvier. As a result, the action potential signal jumps along the axon, from node to node, rather than propagating smoothly, as they do in axons that lack a myelin sheath. The clustering of voltage-gated sodium and potassium ion channels at the nodes permits this behavior.

Saltatory conduction

Since an axon can be unmyelinated or myelinated, the action potential has two methods to travel down the axon. These methods are referred to as continuous conduction for unmyelinated axons, and

for myelinated axons. Saltatory conduction is defined as an action potential moving in discrete jumps down a myelinated axon. This process is outlined as the charge passively spreading to the next node of Ranvier to depolarize it to threshold which will then trigger an action potential in this region which will then passively spread to the next node and so on. Saltatory conduction provides one advantage over conduction that occurs along an axon without myelin sheaths. This is that the increased speed afforded by this mode of conduction assures faster interaction between neurons. On the other hand, depending on the average firing rate of the neuron, calculations show that the energetic cost of maintaining the resting potential of oligodendrocytes can outweigh the energy savings of action potentials. So, axon myelination does not necessarily save energy.

Formation regulation

Paranode regulation via mitochondria accumulation

Mitochondria A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is u ...

and other membranous organelles are normally enriched in the PNP region of peripheral myelinated axons, especially those large caliber axons. The actual physiological role of this accumulation and factors that regulate it are not understood; however, it is known that

mitochondria A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is u ...

are usually present in areas of the cell that expresses a high energy demand. In these same regions, they are also understood to contain growth cones, synaptic terminals, and sites of action potential initiation and regeneration, such as the nodes of Ranvier. In the synaptic terminals, mitochondria produce the ATP needed to mobilize vesicles for neurotransmission. In the nodes of Ranvier,

serve as an important role in impulse conduction by producing the ATP that is essential to maintain the activity of energy-demanding ion pumps. Supporting this fact, about five times more mitochondria are present in the PNP axoplasm of large peripheral axons than in the corresponding internodal regions of these fibers.

Nodal regulation

Via αII-Spectrin

Saltatory conduction In neuroscience, saltatory conduction () is the propagation of action potentials along myelinated axons from one node of Ranvier to the next node, increasing the conduction velocity of action potentials. The uninsulated nodes of Ranvier are th ...

in myelinated axons requires organization of the nodes of Ranvier, whereas voltage-gated sodium channels are highly populated. Studies show that αII-Spectrin, a component of the cytoskeleton is enriched at the nodes and paranodes at early stages and as the nodes mature, the expression of this molecule disappears. It is also proven that αII-Spectrin in the axonal cytoskeleton is absolutely vital for stabilizing sodium channel clusters and organizing the mature node of Ranvier.

Possible regulation via the recognition molecule OMgp

It has been shown previously that OMgp (oligodendrocyte myelin glycoprotein) clusters at nodes of Ranvier and may regulate paranodal architecture, node length and axonal sprouting at nodes. However, a follow-up study showed that the antibody used previously to identify OMgp at nodes crossreacts with another node-enriched component

V2 and that OMgp is not required for the integrity of nodes and paranodes, arguing against the previously reported localization and proposed functions of OMgp at nodes.

Clinical significance

The proteins in these excitable domains of neuron when injured may result in cognitive disorders and various neuropathic ailments.

History

The myelin sheath of long nerves was discovered and named by German

pathological Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in th ...

anatomist

Rudolf Virchow Rudolf Ludwig Carl Virchow (; or ; 13 October 18215 September 1902) was a German physician, anthropologist, pathologist, prehistorian, biologist, writer, editor, and politician. He is known as "the father of modern pathology" and as the founde ...

in 1854. French pathologist and anatomist

Louis-Antoine Ranvier Louis-Antoine Ranvier (2 October 1835 – 22 March 1922) was a French physician, pathologist, anatomist and histologist, who discovered the nodes of Ranvier, regularly spaced discontinuities of the myelin sheath, occurring at varying intervals alo ...

later discovered the nodes, or gaps, in the myelin sheath that now bear his name. Born in

Lyon Lyon,, ; Occitan: ''Lion'', hist. ''Lionés'' also spelled in English as Lyons, is the third-largest city and second-largest metropolitan area of France. It is located at the confluence of the rivers Rhône and Saône, to the northwest of th ...

, Ranvier was one of the most prominent histologists of the late 19th century. Ranvier abandoned pathological studies in 1867 and became an assistant of physiologist

Claude Bernard Claude Bernard (; 12 July 1813 – 10 February 1878) was a French physiologist. Historian I. Bernard Cohen of Harvard University called Bernard "one of the greatest of all men of science". He originated the term '' milieu intérieur'', and the ...

. He was the chairman of General Anatomy at the

Collège de France The Collège de France (), formerly known as the ''Collège Royal'' or as the ''Collège impérial'' founded in 1530 by François I, is a higher education and research establishment ('' grand établissement'') in France. It is located in Paris ...

in 1875. His refined histological techniques and his work on both injured and normal

nerve A nerve is an enclosed, cable-like bundle of nerve fibers (called axons) in the peripheral nervous system. A nerve transmits electrical impulses. It is the basic unit of the peripheral nervous system. A nerve provides a common pathway for the ...

fibers became world-renowned. His observations on fiber nodes and the degeneration and regeneration of cut fibers had a great influence on Parisian neurology at the Salpêtrière. Soon afterwards, he discovered gaps in sheaths of nerve fibers, which were later called the Nodes of Ranvier. This discovery later led Ranvier to careful histological examination of myelin sheaths and Schwann cells.

Additional images

Image:Complete neuron cell diagram en.svg, Complete neuron cell diagram Image:Gray634.png, Medullated nerve fibers stained with silver nitrate

References

External links

Cell Centered Database – Node of Ranvier
* – "PNS, nerve (LM, Medium)" {{Authority control Membrane biology Neurohistology Signal transduction