The Node of Ranvier is the micrometre gap between the glial cells of the myelin sheath. These glial cells are called Schwann cells , and they help to electrically insulate the neuron. The Nodes of Ranvier are only present when the axon of a neuron is myelinated. Myelination allows for an increased rate of action potential transmission due to action potentials "jumping" between Node of Ranvier, this is called saltatory conduction. The movement of sodium ions to depolarize the membrane can only occur at the Node of Ranvier, as the sodium voltage-gated channels are found only at the nodes of Ranvier [2].
The Schwann cells of the myelin sheath block the movement of sodium ions elsewhere along the axon. A distal axonal cytoskeleton forms an intra-axonal boundary that controls axon initial segment assembly. Yoshimura, T. Seidl, A. Mechanisms for adjusting interaural time differences to achieve binaural coincidence detection. Grubb, M. Activity-dependent relocation of the axon initial segment fine-tunes neuronal excitability. Kuba, H. Dutta, D. Regulation of myelin structure and conduction velocity by perinodal astrocytes.
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The node length was approximately proportional to the amount of sodium channel labelling at the node Figure 1I , suggesting that node length may mainly be adjusted by the insertion or removal of membrane containing sodium channels although conceivably it is possible to vary node length in a manner independent of sodium channel trafficking by endo- or exocytosis of vesicles lacking sodium channels in their membrane.
The fact that node lengths are similar over long distances along an axon Figure 2B raises three mechanistic questions. First, when the node length is set to a different mean value in different axons, by what mechanism is the nodal ion channel density controlled Figure 1I? Second, what signal regulates node length, in order to adjust the arrival time of action potentials at the end of the axon? Conceivably a signal could be passed back along the axon from a postsynaptic cell by dynein-based motors, as occurs for BMP signalling from postsynaptic cells to the nuclei of presynaptic neurons Smith et al.
Third, what local molecular mechanism regulates the length of each node, how accurately can this be controlled, and is the internode length shortened when the node is elongated to preserve overall axon length? Interestingly, nodal amyloid precursor protein has been proposed as a regulator of node length Xu et al.
Computer simulations of the propagation of action potentials along myelinated axons Figure 3 show that rather small changes in node length can produce quite significant changes of conduction speed. The range of node lengths seen in the optic nerve 0. The effect of altering node length is larger in cortical axons than in the optic nerve, partly because the 1.
Our data and simulations suggest that modulation of node length could be a viable strategy for adjusting the propagation time of action potentials to meet information processing needs.
Such modulation has been suggested to occur during chronic stress and major depression Miyata et al. Altering node length offers the advantage that very small changes of membrane area, which could easily be produced rapidly by exocytosis or endocytosis at the node, produce large changes of conduction speed.
In comparison, to produce the same speed changes by altering the number of myelin wraps requires the energetically expensive Harris and Attwell, , and probably more time consuming, synthesis or disassembly of a membrane area that is — fold larger. In practice, both mechanisms might be used on different time scales. For the optic nerve, 3 male 8—10 weeks old Sprague-Dawley rats were anaesthetised and perfused through the heart with fixative containing 2.
Back-scattered images were obtained on a scanning electron microscope Hitachi SU with a working distance of 2 mm, 1—1. Four male 8—10 week old rats were anaesthetized with isoflurane and killed by cervical dislocation in accordance with United Kingdom animal experimentation regulations. After decapitation the brain was carefully dissected from the skull and 1 mm thick coronal slices containing the corpus callosum were obtained from the forebrain from 4 to 8 mm rostral of the olfactory bulb using a tissue cutter block.
Immunofluorescence labelling was performed over 3 days with the following primary antibodies: rabbit anti-Na V 1. Pixel size was For node length analysis, confocal images were analysed using ImageJ software. Images were background subtracted and only nodes that lay approximately parallel to the plane of section i. Measuring the angle of the axon to the plane of the slice for a subset of 10 randomly chosen axons showed that the apparent node length measured in this way underestimated the actual node length by only 1.
A maximum intensity projection was generated of the sections in which Caspr labelling was present for a particular node up to five interleaved confocal slices at 0. Node diameter, paranode length and axon diameter were measured using the line tool in ImageJ over Na V 1. Internode length was measured in three dimensions in FIJI using the simple neurite tracer plugin Longair et al. Data were not corrected for tissue shrinkage during fixation.
In brief, the axon is divided into compartments representing the node, paranode and internode. For each time step, current flow across the axonal or total myelin membrane is calculated from the values of voltage and its rate of change , and the membrane capacitance and membrane conductances present per unit length simultaneously solving the differential equations that define activation and inactivation of the voltage-gated currents present at the node , and intracellular and periaxonal axial current flow are calculated from the intracellular or periaxonal resistance per unit length and the gradient of intracellular or periaxonal voltage.
The MATLAB code used can be obtained immediately on request from the authors; it will be written up and documented as a resource for free access from GitHub by August 1st Simulations were carried out as in Bakiri et al.
For simplicity, the node length was usually assumed to be the same at all nodes on the axon, i. The node diameter was set to the mean value measured experimentally, i.
The region between two nodes, This internodal region was divided along its length into 66 and 86 compartments for the optic nerve and the cortex, respectively, the end 2. The internodal axon diameter is larger than the diameter at the node Halter and Clark, ; Berthold and Rydmark, , although this difference is a much smaller percentage for small than for large axons Rydmark and Berthold, The internodal and paranodal axon diameters were set to 0.
Apart from at the paranodes, the internodal axon was assumed to be surrounded by a periaxonal space of thickness 15 nm Robertson, ; Mierzwa et al. This led to the optic nerve and cortical axons having 7 and 5 myelin wraps, respectively assuming a myelin wrap periodicity of The periaxonal space at the paranode, because of the structure of the attachment of the myelin to the axon at the paranode, is thought to comprise Mierzwa et al.
N wraps where N wraps is the number of myelin wraps and d is the axon diameter. A periaxonal space of width w, along a paranode of length L, would have the same resistance as this pathway if.
The effective value of w used to model this spiral pathway for the optic nerve and cortical axons was thus 0. In the main text we present calculations showing that a given change of conduction speed can be produced far more efficiently in terms of the change of membrane area needed by shortening of the node than by adding another wrap of myelin.
Those calculations ignore the possibility that, when the node is shortened, the internode needs to be lengthened by the same amount in order to maintain the axon length. It is unclear whether the sub-micron node length changes postulated in our calculation would actually require remodelling of the adjacent myelin sheath — conceivably slackness in the somewhat non-straight internode would allow the change of node length to be accommodated without a change of internode length, and furthermore node length might change by an eversion of the paranodal loops closest to the node without any other significant change to the myelin sheath reviewed by Arancibia-Carcamo and Attwell, Thus, small changes in nodal length might well occur without major remodelling of the myelin sheath.
Accounting for these area changes and noting that, in this situation, there is no change of total axon length would reduce the ratio of the membrane area changes needed to produce a given speed change when adding a layer of myelin to the sheath versus changing the node length from fold to fold for the optic nerve and from fold to fold for the cortex, but these ratios remain impressively large, and so the energetic argument favouring speed tuning by alteration of the node length still holds.
Assessment of whether the slope of linear regressions differed significantly from zero was obtained using the t-statistic for the slope. In the interests of transparency, eLife includes the editorial decision letter and accompanying author responses. A lightly edited version of the letter sent to the authors after peer review is shown, indicating the most substantive concerns; minor comments are not usually included. The first decision letter after peer review is shown below. Thank you for choosing to send your work entitled "Ranvier node length and myelinated axon conduction speed" for consideration at eLife.
Your full submission has been evaluated by Eve Marder Senior Editor , a Reviewing Editor, and two peer reviewers, and the decision was reached after discussions between the reviewers. Based on our discussions and the individual reviews below, we regret to inform you that we are forced to reject this version of the manuscript. The reviewers were quite conflicted because they really were taken by the aims and goals of the paper, and thought it is potentially important.
Nonetheless, they were troubled by a variety of technical issues that are perhaps captured by their feeling the manuscript suffered by comparing "apples and oranges". Virtually all of the reviewers' comments could be dealt with, but eLife has a strong policy to not require extensive new experimental work when allowing a revision. Therefore, when reviewers really ask for extensive experimental work work that we expect would take more than a month to do , we are forced to reject the manuscript.
This frees the authors to take their manuscript elsewhere if they choose, as it is no longer in consideration at eLife. If, however, you feel in retrospect that the reviewers are, on balance, correct, and if you can deal with these critiques, we would be willing to entertain a new submission, which would be treated as such, at some time in the future. This brief manuscript combines an assessment of the variation in length of nodes of Ranvier the distance separating adjacent internodes along myelinated axons in the rat CNS with modeling to estimate what effect these variations might have on the conduction velocity of action potentials.
The extent and character of myelin is regulated by neuronal activity during development, and there has is renewed interest in the possibility that myelination may be modified throughout life. The effects of altered myelination could be exerted at many levels — myelinated versus unmyelinated, thickness of myelin, length of internodes, and length of nodes, not to mention changes in NaV and Kv densities along axons.
However, little is known about the variations in these parameters in the adult CNS. Defining these variations, exploring how they are affected by life experience and determining their effects on information processing are important goals. Here the authors show that there is greater variation in node length along myelinated axons in brain than in optic nerve, and through modeling show that this variation in brain would be expected to have substantial effects on conduction velocity.
It isn't clear why different methods were used for the two preparations. Some assurance should be provided that the differences seen are not due to the use of different methodologies. In particular, the authors should estimate what error might be induced by analyzing nodes that are in different orientations in the brain samples and indicate how orientation was determined.
It would be helpful if a dozen examples spanning the range of node lengths were illustrated in Figure 1. It isn't clear why different ages were examined.
Oligodendrogenesis and myelination are still ongoing at P30 in brain, raising the possibility that the variation in node length reflects an intermediate developmental state. As internodes grow together to form nodes, some of the longer nodes could represent internodes captured at this stage.
As the development of myelin varies across cortical layers and in different regions of the cortex, the authors should provide information about the regions of the cortex that were examined. Although not quantitative, this could provide some indication of whether NaV density or NaV number is held constant. Also, NaV staining would help clarify if the longest nodes are merely two hemi-nodes prior to consolidation.
Arancibia-Carcamo et al. Numerous recent studies have indicated that myelin in the central nervous system can be generated and modulated well in to adult life. Figure 3 Despite the severe outcome and considerable effect of demyelinating diseases on patients' lives and society, little is known about the mechanism by which myelin is disrupted, how axons degenerate after demyelination, or how remyelination can be facilitated. To establish new treatments for demyelinating diseases, a better understanding of myelin biology and pathology is absolutely required.
How do we structure a research effort to elucidate the mechanisms involved in developmental myelination and demyelinating diseases? We need to develop useful models to test drugs or to modify molecular expression in glial cells.
One strong strategy is to use a culture system. Coculture of dorsal root ganglion neurons and Schwann cells can promote efficient myelin formation in vitro Figure 1E. Researchers can modify the molecular expression in Schwann cells, neurons, or both by various methods, including drugs, enzymes, and introducing genes , and can observe the consequences in the culture dish. Modeling demyelinating disease in laboratory animals is commonly accomplished by treatment with toxins injurious to glial cells such as lysolecithin or cuprizone.
Autoimmune diseases such as MS or autoimmune neuropathies can be reproduced by sensitizing animals with myelin proteins or lipids Figure 3. Some mutant animals with defects in myelin proteins and lipids have been discovered or generated, providing useful disease models for hereditary demyelinating disorders. Further research is required to understand myelin biology and pathology in detail and to establish new treatment strategies for demyelinating neurological disorders.
Myelin can greatly increase the speed of electrical impulses in neurons because it insulates the axon and assembles voltage-gated sodium channel clusters at discrete nodes along its length.
Myelin damage causes several neurological diseases, such as multiple sclerosis. Future studies for myelin biology and pathology will provide important clues for establishing new treatments for demyelinating diseases.
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