Conduction In Myelinated Nerves Research Articles

Autoimmune nodopathy

AbstractAutoimmune nodopathy (AN) is characterized by the presence of autoantibodies targeting molecules essential for saltatory conduction in myelinated nerves. Clinical manifestations of AN show similarities with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), including progressive and symmetrical sensorimotor deficits with electrophysiological demyelinating features in nerve conduction studies. Although no common autoantibodies have yet been identified in CIDP, AN is characterized by autoantibodies that primarily target specific molecular complex structures represented by the Ranvier node and paranode. Furthermore, these autoantibodies, such as neurofascin‐155 (NF155), contactin‐1 (CNTN1), contactin‐related protein 1 (Caspr1), and the CNTN1/Caspr1 complex, are illustrative examples of such autoantibodies. They can disrupt the septal‐like junction of paranodes without triggering cellular immune responses. AN manifests uniquely with symptoms such as ataxia, tremors, and markedly high cerebrospinal fluid (CSF) protein levels, often accompanied by nerve root and cranial nerve hypertrophy. Notably, this condition is resistant to immunotherapies typically effective against CIDP, including intravenous immunoglobulin therapy (IVIg). Current evidence suggests that B‐cell depletion therapies, such as rituximab, could benefit AN treatment. Since it has been suggested that existing treatments for CIDP may be effective in cases of autoantibody positivity of subclasses other than IgG4, CIDP that is resistant to conventional therapy requires novel therapeutic strategies that take into account the possibility of IgG4 autoantibodies.

Teasing of Ventral Spinal Cord White Matter Fibers for the Analysis of Central Nervous System Nodes of Ranvier.

In the central nervous system, the formation of nodes of Ranvier, the short, unmyelinated regions of the axon where voltage-gated sodium channels that mediate saltatory conduction in myelinated nerves are concentrated, is orchestrated by oligodendrocytes, the myelinating cells of the CNS. While transmission electron microscopy remains the gold standard for the study of how the nodal region is organized, this approach is both technically demanding and time-consuming. The availability of antibodies that can be used to label paranodal myelin and the underlying axonal domains that are formed as a result of myelination allowsfor the precise analysis of the nodal region. In this chapter, we describe the method used to prepare teased fiber preparations of CNS white matter. Teased fiber preparations facilitate the rapid, quantitative analysis of a large number of nodes of Ranvier per animal compared to conventional histological approaches.

Saltatory Conduction as an Electrostatic Compressional Wave in the Axoplasm.

Saltatory conduction is an essential phenomenon to facilitate the fast conduction in myelinated nerves. The conventional conductive models assumed electric circuits with local current along the axonal membrane to explain the nerve conduction in unmyelinated nerves. However, whether such models with local current can be also applied to the saltatory conduction in myelinated nerves is unknown. In this report, I propose a new model of saltatory conduction by focusing on the behavior of electric charges in the axoplasm, not limited to the membrane. In myelinated nerves, because of the large internodal length and the low ion channel density in the internodal segment, the whole cross-section of the internodal axoplasm would contribute to the signal conduction. Because the conducted signals originate from the sodium ion influx through the voltage-gated sodium (NaV) channel at the Ranvier's nodes, an individual conducted signal can be described as a single electrostatic compressional wave of positive charges in the internodal axoplasm. Based on this model, the total number of NaV channels in one Ranvier's node would regulate the strength of the wave. Also, the internodal length would be important for the faster conduction in larger myelinated axons. Based on the linear relationships between axonal diameter, internodal length, and conduction velocity, the internodal length would be inversely proportional to the ratio of the transmitted overall wave strength at a Ranvier's node to the original strength at the proximal adjacent node. This new mathematical model may have wide applicability and usability for the conduction in myelinated nerves.

Neurofascin 140 is an embryonic neuronal neurofascin isoform that promotes the assembly of the node of Ranvier.

Rapid nerve conduction in myelinated nerves requires the clustering of voltage-gated sodium channels at nodes of Ranvier. The Neurofascin (Nfasc) gene has a unique role in node formation because it encodes glial and neuronal isoforms of neurofascin (Nfasc155 and Nfasc186, respectively) with key functions in assembling the nodal macromolecular complex. A third neurofascin, Nfasc140, has also been described; however, neither the cellular origin nor function of this isoform was known. Here we show that Nfasc140 is a neuronal protein strongly expressed during mouse embryonic development. Expression of Nfasc140 persists but declines during the initial stages of node formation, in contrast to Nfasc155 and Nfasc186, which increase. Nevertheless, Nfasc140, like Nfasc186, can cluster voltage-gated sodium channels (Nav) at the developing node of Ranvier and can restore electrophysiological function independently of Nfasc155 and Nfasc186. This suggests that Nfasc140 complements the function of Nfasc155 and Nfasc186 in initial stages of the assembly and stabilization of the nodal complex. Further, Nfasc140 is reexpressed in demyelinated white matter lesions of postmortem brain tissue from human subjects with multiple sclerosis. This expands the critical role of the Nfasc gene in the function of myelinated axons and reveals further redundancy in the mechanisms required for the formation of this crucial structure in the vertebrate nervous system.

Differential Stability of PNS and CNS Nodal Complexes When Neuronal Neurofascin Is Lost

Fast, saltatory conduction in myelinated nerves requires the clustering of voltage-gated sodium channels (Nav) at nodes of Ranvier in a nodal complex. The Neurofascin (Nfasc) gene encodes neuronal Neurofascin 186 (Nfasc186) at the node and glial Neurofascin 155 at the paranode, and these proteins play a key role in node assembly. However, their role in the maintenance and stability of the node is less well understood. Here we show that by inducible ablation of Nfasc in neurons in adult mice, Nfasc186 expression is reduced by >99% and 94% at PNS and CNS nodes, respectively. Gliomedin and NrCAM at PNS and brevican at CNS nodes are largely lost with neuronal neurofascin; however, Nav at nodes of Ranvier persist, albeit with ∼40% reduction in expression levels. βIV Spectrin, ankyrin G, and, to a lesser extent, the β1 subunit of the sodium channel, are less affected at the PNS node than in the CNS. Nevertheless, there is a 38% reduction in PNS conduction velocity. Loss of Nfasc186 provokes CNS paranodal disorganization, but this does not contribute to loss of Nav. These results show that Nav at PNS nodes are still maintained in a nodal complex when neuronal neurofascin is depleted, whereas the retention of nodal Nav in the CNS, despite more extensive dissolution of the complex, suggests a supportive role for the partially disrupted paranodal axoglial junction in selectively maintaining Nav at the CNS node.

A Glial Signal Consisting of Gliomedin and NrCAM Clusters Axonal Na + Channels during the Formation of Nodes of Ranvier

Saltatory conduction requires high-density accumulation of Na(+) channels at the nodes of Ranvier. Nodal Na(+) channel clustering in the peripheral nervous system is regulated by myelinating Schwann cells through unknown mechanisms. During development, Na(+) channels are first clustered at heminodes that border each myelin segment, and later in the mature nodes that are formed by the fusion of two heminodes. Here, we show that initial clustering of Na(+) channels at heminodes requires glial NrCAM and gliomedin, as well as their axonal receptor neurofascin 186 (NF186). We further demonstrate that heminodal clustering coincides with a second, paranodal junction (PNJ)-dependent mechanism that allows Na(+) channels to accumulate at mature nodes by restricting their distribution between two growing myelin internodes. We propose that Schwann cells assemble the nodes of Ranvier by capturing Na(+) channels at heminodes and by constraining their distribution to the nodal gap. Together, these two cooperating mechanisms ensure fast and efficient conduction in myelinated nerves.

Restricted growth of Schwann cells lacking Cajal bands slows conduction in myelinated nerves.

Nerve impulses are propagated at nodes of Ranvier in the myelinated nerves of vertebrates. Internodal distances have been proposed to affect the velocity of nerve impulse conduction; however, direct evidence is lacking, and the cellular mechanisms that might regulate the length of the myelinated segments are unknown. Ramón y Cajal described longitudinal and transverse bands of cytoplasm or trabeculae in internodal Schwann cells and suggested that they had a nutritive function. Here we show that internodal growth in wild-type nerves is precisely matched to nerve extension, but disruption of the cytoplasmic bands in Periaxin-null mice impairs Schwann cell elongation during nerve growth. By contrast, myelination proceeds normally. The capacity of wild-type and mutant Schwann cells to elongate is cell-autonomous, indicating that passive stretching can account for the lengthening of the internode during limb growth. As predicted on theoretical grounds, decreased internodal distances strikingly decrease conduction velocities and so affect motor function. We propose that microtubule-based transport in the longitudinal bands of Cajal permits internodal Schwann cells to lengthen in response to axonal growth, thus ensuring rapid nerve impulse transmission.

Completion of myelin compaction, but not the attachment of oligodendroglial processes triggers K channel clustering

The characteristic localization of ion channels is crucial for the propagation of saltatory conduction in myelinated nerves. Voltage-gated Na+ channels are located at nodes of Ranvier while voltage-gated K+ channels are mainly found at juxtaparanodal regions. Recently, a humoral factor secreted by oligodendrocytes has been reported to induce clustering of Na+ channels in CNS axons. However, the molecular mechanisms for K+ channel clustering as well as the role of oligodendrocytes are still uncertain. To clarify whether myelin sheath itself can induce the distinct distribution of K+ channels, we have investigated the localization of K+ channels in adult and developing mouse optic nerves. The CNS axons from chronic demyelinating and hypomyelinating mice were also examined to determine if myelin sheaths were required for the maintenance of clusters. In all cases, the K+ channel clustering correlated well with compact myelin, but not with the presence of oligodendrocytes, suggesting that, in contrast to Na+ channel clustering, the formation of compact myelin is required for initiation as well as maintenance of K+ channel clustering. In addition, postsynaptic density protein-95 (PSD-95) or its highly related protein was found colocalized with K+ channels, suggesting that it may interact with K+ channels to form clusters at juxtaparanodal regions. J. Neurosci. Res. 58:752–764, 1999. © 1999 Wiley-Liss, Inc.

Completion of myelin compaction, but not the attachment of oligodendroglial processes triggers K+ channel clustering

The characteristic localization of ion channels is crucial for the propagation of saltatory conduction in myelinated nerves. Voltage-gated Na(+) channels are located at nodes of Ranvier while voltage-gated K(+) channels are mainly found at juxtaparanodal regions. Recently, a humoral factor secreted by oligodendrocytes has been reported to induce clustering of Na(+) channels in CNS axons. However, the molecular mechanisms for K(+) channel clustering as well as the role of oligodendrocytes are still uncertain. To clarify whether myelin sheath itself can induce the distinct distribution of K(+) channels, we have investigated the localization of K(+) channels in adult and developing mouse optic nerves. The CNS axons from chronic demyelinating and hypomyelinating mice were also examined to determine if myelin sheaths were required for the maintenance of clusters. In all cases, the K(+) channel clustering correlated well with compact myelin, but not with the presence of oligodendrocytes, suggesting that, in contrast to Na(+) channel clustering, the formation of compact myelin is required for initiation as well as maintenance of K(+) channel clustering. In addition, postsynaptic density protein-95 (PSD-95) or its highly related protein was found colocalized with K(+) channels, suggesting that it may interact with K(+) channels to form clusters at juxtaparanodal regions.