Nodes Of Ranvier Research Articles

A Non-local Model of the Propagation of Action Potentials in Myelinated Neurons

Myelinated neurons are characterized by the presence of myelin, a multilaminated wrapping around the axons formed by specialized neuroglial cells. Myelin acts as an electrical insulator and therefore, in myelinated neurons, the action potentials do not propagate within the axons but happen only at the nodes of Ranvier which are gaps in the axonal myelination. Recent advancements in brain science have shown that the shapes, timings, and propagation speeds of these so-called saltatory action potentials are controlled by various biochemical interactions among neurons, glial cells and the extracellular space. Given the complexity of brain’s structure and processes, the work hypothesis made in this paper is that non-local effects are involved in the optimal propagation of action potentials. A non- local model of the action potentials propagation in myelinated neurons is proposed that involves spatial derivatives of fractional order. The effects of non- locality on the distribution of the membrane potential are investigated using numerical simulations.

Amplification of terahertz/infrared field at the nodes of Ranvier for myelinated nerve

The myelination of axons was the last major evolution in the vertebrate nervous system. Myelin promotes the speed of action potential by two orders, and modulates the conduction of neurons, important for learning new skills. However, the intrinsic mechanism for high-speed information propagation in myelin in the nervous systems is still unclear. We propose that myelinated nerve fibres serve as dielectric waveguides for the high-frequency electromagnetic information in a certain mid-infrared to terahertz spectral range. Based on the structure characteristics of myelinated nerve composed of periodic nodes of Ranvier and myelin sheath, the energy for the signal propagation is supplied and amplified when crossing the nodes of Ranvier via a periodic relay. In this work, we exploit the quasi-quantum model of amplification for neural terahertz/infrared information at the nodes of Ranvier, and prove the existence of biomolecular ensemble for three-energy-level amplification, revealing the essential mechanism of high-speed electromagnetic information transmitting in myelinated nerves.

Three-dimensional architecture of human diabetic peripheral nerves revealed by X-ray phase contrast holographic nanotomography

A deeper knowledge of the architecture of the peripheral nerve with three-dimensional (3D) imaging of the nerve tissue at the sub-cellular scale may contribute to unravel the pathophysiology of neuropathy. Here we demonstrate the feasibility of X-ray phase contrast holographic nanotomography to enable 3D imaging of nerves at high resolution, while covering a relatively large tissue volume. We show various subcomponents of human peripheral nerves in biopsies from patients with type 1 and 2 diabetes and in a healthy subject. Together with well-organized, parallel myelinated nerve fibres we show regenerative clusters with twisted nerve fibres, a sprouted axon from a node of Ranvier and other specific details. A novel 3D construction (with movie created) of a node of Ranvier with end segment of a degenerated axon and sprout of a regenerated one is captured. Many of these architectural elements are not described in the literature. Thus, X-ray phase contrast holographic nanotomography enables identifying specific morphological structures in 3D in peripheral nerve biopsies from a healthy subject and from patients with type 1 and 2 diabetes.

Independent anterograde transport and retrograde cotransport of domain components of myelinated axons.

Neurons are highly polarized cells organized into functionally and molecularly distinct domains. A key question is whether the multiprotein complexes that comprise these domains are preassembled, transported, and inserted as a complex or whether their components are transported independently and assemble locally. Here, we have dynamically imaged, in pairwise combinations, the vesicular transport of fluorescently tagged components of the nodes of Ranvier and other myelinated axonal domains in sensory neurons cultured alone or together with Schwann cells at the onset of myelination. In general, most proteins are transported independently in the anterograde direction. In contrast, there is substantial cotransport of proteins from distinct domains in the retrograde direction likely due to coendocytosis along the axon. Early myelination did not substantially change these patterns of transport, although it increased the overall numbers of axonal transport vesicles. Our results indicate domain components are transported in separate vesicles for local assembly, not as preformed complexes, and implicate endocytosis along axons as a mechanism of clearance.

The Frog Motor Nerve Terminal Has Very Brief Action Potentials and Three Electrical Regions Predicted to Differentially Control Transmitter Release.

The action potential (AP) waveform controls the opening of voltage-gated calcium channels and contributes to the driving force for calcium ion flux that triggers neurotransmission at presynaptic nerve terminals. Although the frog neuromuscular junction (NMJ) has long been a model synapse for the study of neurotransmission, its presynaptic AP waveform has never been directly studied, and thus the AP waveform shape and propagation through this long presynaptic nerve terminal are unknown. Using a fast voltage-sensitive dye, we have imaged the AP waveform from the presynaptic terminal of male and female frog NMJs and shown that the AP is very brief in duration and actively propagated along the entire length of the terminal. Furthermore, based on measured AP waveforms at different regions along the length of the nerve terminal, we show that the terminal is divided into three distinct electrical regions: A beginning region immediately after the last node of Ranvier where the AP is broadest, a middle region with a relatively consistent AP duration, and an end region near the tip of nerve terminal branches where the AP is briefer. We hypothesize that these measured changes in the AP waveform along the length of the motor nerve terminal may explain the proximal-distal gradient in transmitter release previously reported at the frog NMJ.SIGNIFICANCE STATEMENT The AP waveform plays an essential role in determining the behavior of neurotransmission at the presynaptic terminal. Although the frog NMJ is a model synapse for the study of synaptic transmission, there are many unknowns centered around the shape and propagation of its presynaptic AP waveform. Here, we demonstrate that the presynaptic terminal of the frog NMJ has a very brief AP waveform and that the motor nerve terminal contains three distinct electrical regions. We propose that the changes in the AP waveform as it propagates along the terminal can explain the proximal-distal gradient in transmitter release seen in electrophysiological studies.

Ultrastructural mechanisms of macrophage-induced demyelination in Guillain-Barré syndrome

ObjectiveTo describe the pathological features of Guillain-Barré syndrome focusing on macrophage-associated myelin lesions.MethodsLongitudinal sections of sural nerve biopsy specimens from 11 patients with acute inflammatory demyelinating polyneuropathy (AIDP) exhibiting macrophage-associated...

Saltatory Conduction: Jumping to New Conclusions.

Rapid and efficient saltatory action potential conduction depends on the myelin sheath and clustered Na+ channels at nodes of Ranvier. A new study convincingly shows that the periaxonal space is a necessary conductive component to accurately model myelinated axon physiology and saltatory conduction.

SPARC ‐ The Functional Anatomy of Murine Myelinated Renal Afferents

Perhaps because they are a small minority of the total population of renal afferents, myelinated renal afferents (MRA ) have been the least studied. Yet, they are promising targets for neuromodulation because of their low thresholds for electrical stimulation. We are studying the calibers, branching patterns, terminal morphologies, and intrarenal targets of MRA. We identify the myelin sheaths and axons of MRA using antibodies to myelin protein zero and heavy‐chain neurofilament, respectively. The diameters of a majority of MRA range between 1 and 4 u. The diameters of a small minority range between 6 and 10u. Thus, the diameters of MRA are distinctly bimodal. Unmyelinated terminal segments of MRA arise from the myelinated segments of axons at two sites. First, an unmyelinated segment of axon projects from the end of each MRA. Second, unmyelinated segments arise as axon collaterals at nodes of Ranvier along the course of the myelinated axon. Most unmyelinated segments end without any terminal specialization. However, some terminate in small “bulbs, that are approximately twice the diameter of the axon. We have not observed receptor‐related, connective tissue specializations surrounding either type of termination. The distal myelinated portions of MRA are frequently tortuous, sometimes forming hairpin turns and loops. These complex features result in spatial concentrations of nodes of Ranvier, concentrations of unmyelinated collaterals, and concentrations of receptors. A marked narrowing at the origin of each unmyelinated segment suggests the presence of a spike‐initiation zone. The majority of MRA terminate deep in the renal cortex, most often in the extracellular space and frequently within bundles of connective tissue. Some terminations closely appose, but never penetrate, the renal tubular system. However, a small number of MRA appear to penetrate the walls of small arteries and venules. Terminations of MRA show no consistent relationship to glomeruli. The functions of MRA are, thus far, uncertain. Their terminations in the extracellular space would permit them to respond to changes in the composition of the extracellular fluid. However, their associations with connective tissue in the extracellular space could also provide them with mechanoreceptor properties. Their presence in the walls of the vasculature could mediate either chemoreceptor or mechanoreceptor functions. The distinctly bimodal distribution of the diameters of MRA suggests that they may participate in more than one physiological function. From a clinical perspective, the differences in stimulation thresholds afforded by those differences in axon caliber could facilitate selective neuromodulation of multiple physiological processes.Support or Funding InformationSupported by SPARC Award 1U01DK116320‐02, JW Osborn, Jr., PI

Thrombin regulates the ability of Schwann cells to support neuritogenesis and to maintain the integrity of the nodes of Ranvier.

Schwann cells (SC) are characterized by a remarkable plasticity that enables them to promptly respond to nerve injury promoting axonal regeneration. In peripheral nerves after damage SC convert to a repair-promoting phenotype activating a sequence of supportive functions that drive myelin clearance, prevent neuronal death, and help axon growth and guidance. Regeneration of peripheral nerves after damage correlates inversely with thrombin levels. Thrombin is not only the key regulator of the coagulation cascade but also a protease with hormone- like activities that affects various cells of the central and peripheral nervous system mainly through the protease-activated receptor 1 (PAR1). Aim of the present study was to investigate if and how thrombin could affect the axon supportive functions of SC. In particular, our results show that the activation of PAR1 in rat SC cultures with low levels of thrombin or PAR1 agonist peptides induces the release of molecules, which favor neuronal survival and neurite elongation. Conversely, the stimulation of SC with high levels of thrombin or PAR1 agonist peptides drives an opposite effect inducing SC to release factors that inhibit the extension of neurites. Moreover, high levels of thrombin administered to sciatic nerve ex vivo explants induce a dramatic change in SC morphology causing disappearance of the Cajal bands, enlargement of the Schmidt-Lanterman incisures and calcium-mediated demyelination of the paranodes. Our results indicate thrombin as a novel modulator of SC plasticity potentially able to favor or inhibit SC pro-regenerative properties according to its level at the site of lesion.

TRPV1 Tunes Optic Nerve Axon Excitability in Glaucoma.

The transient receptor potential vanilloid member 1 (TRPV1) in the central nervous system may contribute to homeostatic plasticity by regulating intracellular Ca2+, which becomes unbalanced in age-related neurodegenerative diseases, including Alzheimer’s and Huntington’s. Glaucomatous optic neuropathy – the world’s leading cause of irreversible blindness – involves progressive degeneration of retinal ganglion cell (RGC) axons in the optic nerve through sensitivity to stress related to intraocular pressure (IOP). In models of glaucoma, genetic deletion of TRPV1 (Trpv1–/–) accelerates RGC axonopathy in the optic projection, whereas TRPV1 activation modulates RGC membrane polarization. In continuation of these studies, here, we found that Trpv1–/– increases the compound action potential (CAP) of optic nerves subjected to short-term elevations in IOP. This IOP-induced increase in CAP was not directly due to TRPV1 channels in the optic nerve, because the TRPV1-selective antagonist iodoresiniferatoxin had no effect on the CAP for wild-type optic nerve. Rather, the enhanced CAP in Trpv1–/– optic nerve was associated with increased expression of the voltage-gated sodium channel subunit 1.6 (NaV1.6) in longer nodes of Ranvier within RGC axons, rendering Trpv1–/– optic nerve relatively insensitive to NaV1.6 antagonism via 4,9-anhydrotetrodotoxin. These results indicate that with short-term elevations in IOP, Trpv1–/– increases axon excitability through greater NaV1.6 localization within longer nodes. In neurodegenerative disease, native TRPV1 may tune NaV expression in neurons under stress to match excitability to available metabolic resources.

Precise Spatiotemporal Control of Nodal Na+ Channel Clustering by Bone Morphogenetic Protein-1/Tolloid-like Proteinases

During development of the peripheral nervous system (PNS), Schwann-cell-secreted gliomedin induces the clustering of Na+ channels at the edges of each myelin segment to form nodes of Ranvier. Here we show that bone morphogenetic protein-1 (BMP1)/Tolloid (TLD)-like proteinases confine Na+ channel clustering to these sites by negatively regulating the activity of gliomedin. Eliminating the Bmp1/TLD cleavage site in gliomedin or treating myelinating cultures with a Bmp1/TLD inhibitor results in the formation of numerous ectopic Na+ channel clusters along axons that are devoid of myelin segments. Furthermore, genetic deletion of Bmp1 and Tll1 genes in mice using a Schwann-cell-specific Cre causes ectopic clustering of nodal proteins, premature formation of heminodes around early ensheathing Schwann cells, and altered nerve conduction during development. Our results demonstrate that by inactivating gliomedin, Bmp1/TLD functions as an additional regulatory mechanism to ensure the correct spatial and temporal assembly of PNS nodes of Ranvier.

The formation of paranodal spirals at the ends of CNS myelin sheaths requires the planar polarity protein Vangl2.

During axonal ensheathment, noncompact myelin channels formed at lateral edges of the myelinating process become arranged into tight paranodal spirals that resemble loops when cut in cross section. These adhere to the axon, concentrating voltage-dependent sodium channels at nodes of Ranvier and patterning the surrounding axon into distinct molecular domains. The signals responsible for forming and maintaining the complex structure of paranodal myelin are poorly understood. Here, we test the hypothesis that the planar cell polarity determinant Vangl2 organizes paranodal myelin. We show that Vangl2 is concentrated at paranodes and that, following conditional knockout of Vangl2 in oligodendrocytes, the paranodal spiral loosens, accompanied by disruption to the microtubule cytoskeleton and mislocalization of autotypic adhesion molecules between loops within the spiral. Adhesion of the spiral to the axon is unaffected. This results in disruptions to axonal patterning at nodes of Ranvier, paranodal axon diameter and conduction velocity. When taken together with our previous work showing that loss of the apico-basal polarity protein Scribble has the opposite phenotype-loss of axonal adhesion but no effect on loop-loop autotypic adhesion-our results identify a novel mechanism by which polarity proteins control the shape of nodes of Ranvier and regulate conduction in the CNS.

An alternative mechanism of early nodal clustering and myelination onset in GABAergic neurons of the central nervous system.

In vertebrates, fast saltatory conduction along myelinated axons relies on the node of Ranvier. How nodes assemble on CNS neurons is not yet fully understood. We previously described that node-like clusters can form prior to myelin deposition in hippocampal GABAergic neurons and are associated with increased conduction velocity. Here, we used a live imaging approach to characterize the intrinsic mechanisms underlying the assembly of these clusters prior to myelination. We first demonstrated that their components can partially preassemble prior to membrane targeting and determined the molecular motors involved in their trafficking. We then demonstrated the key role of the protein β2Nav for node-like clustering initiation. We further assessed the fate of these clusters when myelination proceeds. Our results shed light on the intrinsic mechanisms involved in node-like clustering prior to myelination and unravel a potential role of these clusters in node of Ranvier formation and in guiding myelination onset.

Anti‐nodal/paranodal antibodies in human demyelinating disorders

AbstractAnti‐nodal/paranodal antibodies have been reported in human demyelinating disorders. Anti‐nodal protein antibodies, namely, anti‐neurofascin (NF) 186 antibodies and antibodies against paranodal proteins, such as NF155, contactin 1 (CNTN1), and contactin‐associated protein 1 (CASPR1), are found in subsets of chronic inflammatory demyelinating polyneuropathy (CIDP). In particular, CIDP patients with IgG4 anti‐NF155 antibodies and those with IgG4 anti‐CNTN1 antibodies commonly show sensory ataxia, severe demyelination on nerve conduction studies, very high cerebrospinal (CSF) protein levels and poor response to intravenous immunoglobulin. However, younger age at onset, higher frequency of tremor, and nerve root hypertrophy are characteristic of anti‐NF155 antibody–positive CIDP, whereas anti‐CNTN1 antibody–positive CIDP is characterized by higher age at onset, early axonal damage, subacute aggressive course, and concurrence of membranous nephropathy. Interestingly, anti‐NF155 antibody–positive CIDP occasionally accompanies central nervous system lesions suggestive of demyelination. Such cases are termed combined central and peripheral demyelination. Both CIDP with anti‐NF155 antibodies and CIDP with anti‐CNTN1 antibodies usually demonstrate detachment of terminal loops from the axolemma at the node of Ranvier in biopsied sural nerves. IgG4 in vivo is monovalent and bispecific and lacks complement‐binding capability; therefore, IgG4 autoantibodies can only interfere with protein–protein interactions. This property of IgG4 explains the sural nerve pathology but the reasons behind nerve root hypertrophy and CSF protein increase are not known. Recently, we found significant elevation of both Th1 and Th2 cytokines in CSF from anti‐NF155 antibody–positive CIDP patients, indicating T‐cell involvement in this condition.

Nodal β spectrins are required to maintain Na+ channel clustering and axon integrity.

Clustered ion channels at nodes of Ranvier are critical for fast action potential propagation in myelinated axons. Axon-glia interactions converge on ankyrin and spectrin cytoskeletal proteins to cluster nodal Na+ channels during development. However, how nodal ion channel clusters are maintained is poorly understood. Here, we generated mice lacking nodal spectrins in peripheral sensory neurons to uncouple their nodal functions from their axon initial segment functions. We demonstrate a hierarchy of nodal spectrins, where β4 spectrin is the primary spectrin and β1 spectrin can substitute; each is sufficient for proper node organization. Remarkably, mice lacking nodal β spectrins have normal nodal Na+ channel clustering during development, but progressively lose Na+ channels with increasing age. Loss of nodal spectrins is accompanied by an axon injury response and axon deformation. Thus, nodal spectrins are required to maintain nodal Na+ channel clusters and the structural integrity of axons.

Electrophysiological features of chronic inflammatory demyelinating polyradiculoneuropathy associated with IgG4 antibodies targeting neurofascin 155 or contactin 1 glycoproteins

ObjectiveChronic inflammatory demyelinating polyradiculoneuropathies (CIDP) with antibodies against neurofascin 155 (Nfasc155) or contactin-1 (CNTN1) have distinctive clinical features. Knowledge on their electrophysiological characteristics is still scarce. In this study, we are investigating whether these patients have specific electrophysiological characteristics. MethodsThe electrophysiological data from 13 patients with anti-Nfasc155 IgG4 antibodies, 9 with anti-CNTN1 IgG4 antibodies were compared with those of 40 consecutive CIDP patients without antibodies. ResultsAll the patients with antibodies against Nfasc155 or CNTN1 fulfilled the EFNS/PNS electrodiagnostic criteria for definite CIDP. There was no electrophysiological difference between patients with anti-CNTN1 and anti-Nfasc155 antibodies. Nerve conduction abnormalities were heterogeneously distributed along nerves trunks and roots. They were more pronounced than in CIDP without antibodies. Motor conduction velocity on median nerve <24 m/s or motor velocity on ulnar nerve <26 m/s or motor distal latency on ulnar nerve >7.4 ms were predictive of positive antibodies against the node of Ranvier with a sensitivity of 59% and a specificity of 93%. ConclusionsMarked conduction abnormalities may suggest the presence of positive antibodies against the node of Ranvier. SignificanceAnti-Nfasc155 and anti-CNTN1 antibodies target the the paranodal axo-glial domain but are associated with nerve conduction abnormalities mimicking a “demyelinating” neuropathy.

A mechanism for neurofilament transport acceleration through nodes of Ranvier

Neurofilaments are abundant space-filling cytoskeletal polymers in axons that are transported along microtubule tracks. Neurofilament transport is accelerated at nodes of Ranvier, where axons are locally constricted. Strikingly, these constrictions are accompanied by sharp decreases in neurofilament number, no decreases in microtubule number, and increases in the packing density of these polymers, which collectively bring nodal neurofilaments closer to their microtubule tracks. We hypothesize that this leads to an increase in the proportion of time that the filaments spend moving and that this can explain the local acceleration. To test this, we developed a stochastic model of neurofilament transport that tracks their number, kinetic state, and proximity to nearby microtubules in space and time. The model assumes that the probability of a neurofilament moving is dependent on its distance from the nearest available microtubule track. Taking into account experimentally reported numbers and densities for neurofilaments and microtubules in nodes and internodes, we show that the model is sufficient to explain the local acceleration of neurofilaments within nodes of Ranvier. This suggests that proximity to microtubule tracks may be a key regulator of neurofilament transport in axons, which has implications for the mechanism of neurofilament accumulation in development and disease.

The Subcellular Localization of Sodium Channels & Potassium Channels in the Nodes of Ranvier

The Subcellular Localization of Sodium Channels & Potassium Channels in the Nodes of Ranvier

Bridging the Molecular-Cellular Gap in Understanding Ion Channel Clustering.

The clustering of many voltage-dependent ion channel molecules at unique neuronal membrane sites such as axon initial segments, nodes of Ranvier, or the post-synaptic density, is an active process mediated by the interaction of ion channels with scaffold proteins and is of immense importance for electrical signaling. Growing evidence indicates that the density of ion channels at such membrane sites may affect action potential conduction properties and synaptic transmission. However, despite the emerging importance of ion channel density for electrical signaling, how ion channel-scaffold protein molecular interactions lead to cellular ion channel clustering, and how this process is regulated are largely unknown. In this review, we emphasize that voltage-dependent ion channel density at native clustering sites not only affects the density of ionic current fluxes but may also affect the conduction properties of the channel and/or the physical properties of the membrane at such locations, all changes that are expected to affect action potential conduction properties. Using the concrete example of the prototypical Shaker voltage-activated potassium channel (Kv) protein, we demonstrate how insight into the regulation of cellular ion channel clustering can be obtained when the molecular mechanism of ion channel-scaffold protein interaction is known. Our review emphasizes that such mechanistic knowledge is essential, and when combined with super-resolution imaging microscopy, can serve to bridge the molecular-cellular gap in understanding the regulation of ion channel clustering. Pressing questions, challenges and future directions in addressing ion channel clustering and its regulation are discussed.

Feasibility of differentially measuring afferent and efferent neural activity with a single nerve cuff electrode

Objective. Advances in electrode technology have facilitated the development of neuroprostheses for restoring motor/sensory function in disabled individuals. Information extracted from a whole nerve, recorded using cuffs, can provide signals that control the operation of neuroprostheses. However, the amount of information that can be extracted from a tripolar cuff—which provides the highest signal-to-noise ratio (SNR)—is limited. The physical symmetry of the tripolar cuff results in neural recordings that cannot differentiate afferent versus efferent signals. In this study, we introduced a tetrapolar cuff to achieve low-noise and directionally sensitive recording. Approach. The tetrapolar cuff was initially designed using a computational approach. A finite element model was used to solve the electric potential generated at the electrode contacts by active electrical sources, such as the nodes of Ranvier and an artifact noise source. The resulting single fiber action potentials (SFAPs) and artifact noise signals (ANS) were used to characterize the performance of the tetrapolar configuration of the electrode length (EL) and electrode edge length (EEL) on simulated SFAP and ANS. The feasibility of using a tetrapolar cuff to differentiate afferent/efferent action potentials by applying potassium chloride in anesthetized rats was also investigated. Main results. Both the computational and experimental results of this study indicated that directional recording can be achieved using a tetrapolar cuff. Testing different design criteria (e.g. EL and EEL) showed that at EL values above 15 mm and EEL ⩾ 2 mm, the tetrapolar cuffs can yield larger SNRs than equally-sized tripolar cuffs. Significance. This study indicated that low-noise directionally sensitive measurement of neural activity can be achieved with a tetrapolar cuff. The experimental results confirmed the feasibility of using a tetrapolar cuff to differentiate afferent/efferent signals by applying potassium chloride. Further work is needed to determine whether the tetrapolar cuff can differentiate afferent/efferent physiologically elicited neural activities.