Explore the vast range of titles available.

The efficient propagation of action potentials along nervous fibers is necessary for animals to interact with the environment with timeliness and precision. Myelination of axons is an essential step to ensure fast action potential propagation by saltatory conduction, a process that requires highly concentrated voltage-gated sodium channels at the nodes of Ranvier. Recent studies suggest that the clustering of sodium channels can influence axonal impulse conduction in both myelinated and unmyelinated fibers, which could have major implications in disease, particularly demyelinating pathology. This comprehensive review summarizes the mechanisms governing the clustering of sodium channels at the peripheral and central nervous system nodes and the specific roles of their clustering in influencing action potential conduction. We further highlight the classical biophysical parameters implicated in conduction timing, followed by a detailed discussion on how sodium channel clustering along unmyelinated axons can impact axonal impulse conduction in both physiological and pathological contexts.

The speed of impulse transmission is critical for optimal neural circuit function, but it is unclear how the appropriate conduction velocity is established in individual axons. The velocity of impulse transmission is influenced by the thickness of the myelin sheath and the morphology of electrogenic nodes of Ranvier along axons. Here we show that myelin thickness and nodal gap length are reversibly altered by astrocytes, glial cells that contact nodes of Ranvier. Thrombin-dependent proteolysis of a cell adhesion molecule that attaches myelin to the axon (neurofascin 155) is inhibited by vesicular release of thrombin protease inhibitors from perinodal astrocytes. Transgenic mice expressing a dominant-negative fragment of VAMP2 in astrocytes, to reduce exocytosis by 50%, exhibited detachment of adjacent paranodal loops of myelin from the axon, increased nodal gap length, and thinning of the myelin sheath in the optic nerve. These morphological changes alter the passive cable properties of axons to reduce conduction velocity and spike-time arrival in the CNS in parallel with a decrease in visual acuity. All effects were reversed by the thrombin inhibitor Fondaparinux. Similar results were obtained by viral transfection of tetanus toxin into astrocytes of rat corpus callosum. Previously, it was unknown how the myelin sheath could be thinned and the functions of perinodal astrocytes were not well understood. These findings describe a form of nervous system plasticity in which myelin structure and conduction velocity are adjusted by astrocytes. The thrombin-dependent cleavage of neurofascin 155 may also have relevance to myelin disruption and repair.

Healthy nodes of Ranvier are crucial for action potential propagation along myelinated axons, both in the central and in the peripheral nervous system. Surprisingly, the node of Ranvier has often been neglected when describing CNS disorders, with most pathologies classified simply as being due to neuronal defects in the grey matter or due to oligodendrocyte damage in the white matter. However, recent studies have highlighted changes that occur in pathological conditions at the node of Ranvier, and at the associated paranodal and juxtaparanodal regions where neurons and myelinating glial cells interact. Lengthening of the node of Ranvier, failure of the electrically resistive seal between the myelin and the axon at the paranode, and retraction of myelin to expose voltage-gated K + channels in the juxtaparanode, may contribute to altering the function of myelinated axons in a wide range of diseases, including stroke, spinal cord injury and multiple sclerosis. Here, we review the principles by which the node of Ranvier operates and its molecular structure, and thus explain how defects at the node and paranode contribute to neurological disorders.

Myelination speeds conduction of the nerve impulse, enhancing cognitive power. Changes of white matter structure contribute to learning, and are often assumed to reflect an altered number of myelin wraps. We now show that, in rat optic nerve and cerebral cortical axons, the node of Ranvier length varies over a 4.4-fold and 8.7-fold range respectively and that variation of the node length is much less along axons than between axons. Modelling predicts that these node length differences will alter conduction speed by ~20%, similar to the changes produced by altering the number of myelin wraps or the internode length. For a given change of conduction speed, the membrane area change needed at the node is >270-fold less than that needed in the myelin sheath. Thus, axon-specific adjustment of node of Ranvier length is potentially an energy-efficient and rapid mechanism for tuning the arrival time of information in the CNS. Information is transmitted around the nervous system as electrical signals passing along nerve cells. A fatty substance called myelin, which is wrapped around the nerve cells, increases the speed with which the signals travel along the nerve cells. This allows us to think and move faster than we would otherwise be able to do. The electrical signals start at small “nodes” between areas of myelin wrapping. Originally it was thought that we learn things mainly as a result of changes in the strength of connections between nerve cells, but recently it has been proposed that changes in myelin wrapping could also contribute to learning. Arancibia-Cárcamo, Ford, Cossell et al. investigated how much node structure varies in rat nerve cells, and whether differences in the length of nodes can fine-tune the activity of the nervous system. The experiments show that rat nerve cells do indeed have nodes with a range of different lengths. Calculations show that this could result in electrical signals moving at different speeds through different nerve cells. These findings raise the possibility that nerve cells actively alter the length of their nodes in order to alter their signal speed. The next step is to try to show experimentally that this happens during learning in animals.

Large-diameter myelinated fibers in sciatic nerves are composed of both Aα/β-afferent fibers and Aα-efferent fibers to convey sensory and motor impulses, respectively, via saltatory conduction for rapid leg responses. Saltatory conduction and electrophysiological properties at the nodes of Ranvier (NRs) of these sciatic nerve fibers have not been directly studied. We used ex vivo sciatic nerve preparations from rats and applied patch-clamp recordings at the NRs of both Aα/β-afferent fibers and Aα-efferent fibers in the sciatic nerves to characterize their saltatory conduction and intrinsic electrophysiological properties. The velocity and frequency of saltatory conduction in both types of fibers were similar. Resting membrane potentials (RMPs), input resistance, action potential (AP) threshold, and AP rheobase were also not significantly different at the NRs of the two types of fibers in the sciatic nerves. In comparison with Aα/β-afferent fibers, Aα-efferent fibers in the sciatic nerves show higher amplitude and broader width of APs at their NRs. At the NRs of both types of fibers, depolarizing voltages evoked transient inward currents followed by non-inactivating outward currents, and the inward currents and non-inactivating outward currents at the NRs were not significantly different between the two types of fibers. Using AP-clamp, inward currents during AP upstroke were found to be insignificant difference, but amplitudes of non-inactivating outward currents during AP repolarization were significantly lower at the NRs of Aα-efferent fibers than at the NRs of Aα/β-afferent fibers in the sciatic nerves. Collectively, saltatory conduction, ionic currents, and intrinsic electrophysiological properties at the NRs of Aα/β-afferent fibers and Aα-efferent fibers in the sciatic nerves are generally similar, but some differences were also observed.

BackgroundMonoclonal antibodies (mAbs) towards CGRP or the CGRP receptor show good prophylactic antimigraine efficacy. However, their site of action is still elusive. Due to lack of passage of mAbs across the blood-brain barrier the trigeminal system has been suggested a possible site of action because it lacks blood-brain barrier and hence is available to circulating molecules. The trigeminal ganglion (TG) harbors two types of neurons; half of which store CGRP and the rest that express CGRP receptor elements (CLR/RAMP1).MethodsWith specific immunohistochemistry methods, we demonstrated the localization of CGRP, CLR, RAMP1, and their locations related to expression of the paranodal marker contactin-associated protein 1 (CASPR). Furthermore, we studied functional CGRP release separately from the neuron soma and the part with only nerve fibers of the trigeminal ganglion, using an enzyme-linked immunosorbent assay.ResultsAntibodies towards CGRP and CLR/RAMP1 bind to two different populations of neurons in the TG and are found in the C- and the myelinated Aδ-fibers, respectively, within the dura mater and in trigeminal ganglion (TG). CASPR staining revealed paranodal areas of the different myelinated fibers inhabiting the TG and dura mater. Double immunostaining with CASPR and RAMP1 or the functional CGRP receptor antibody (AA58) revealed co-localization of the two peptides in the paranodal region which suggests the presence of the CGRP-receptor. Double immunostaining with CGRP and CASPR revealed that thin C-fibers have CGRP-positive boutons which often localize in close proximity to the nodal areas of the CGRP-receptor positive Aδ-fibers. These boutons are pearl-like synaptic structures, and we show CGRP release from fibers dissociated from their neuronal bodies. In addition, we found that adjacent to the CGRP receptor localization in the node of Ranvier there was PKA immunoreactivity (kinase stimulated by cAMP), providing structural possibility to modify conduction activity within the Aδ-fibers.ConclusionWe observed a close relationship between the CGRP containing C-fibers and the Aδ-fibers containing the CGRP-receptor elements, suggesting a point of axon-axon interaction for the released CGRP and a site of action for gepants and the novel mAbs to alleviate migraine.

Discovery of disease-associated autoantibodies has transformed the clinical management of a variety of neurological disorders. Detection of autoantibodies aids diagnosis and allows patient stratification resulting in treatment optimization. In the last years, a set of autoantibodies against proteins located at the node of Ranvier has been identified in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). These antibodies target neurofascin, contactin1, or contactin-associated protein 1, and we propose to name CIDP patients with these antibodies collectively as seropositive. They have unique clinical characteristics that differ from seronegative CIDP. Moreover, there is compelling evidence that autoantibodies are relevant for the pathogenesis. In this article, we review the current knowledge on the characteristics of autoantibodies against the node of Ranvier proteins and their clinical relevance in CIDP. We start with a description of the structure of the node of Ranvier followed by a summary of assays used to identify seropositive patients; and then, we describe clinical features and characteristics linked to seropositivity. We review knowledge on the role of these autoantibodies for the pathogenesis with relevance for the emerging concept of nodopathy/paranodopathy and summarize the treatment implications.

The complex manifestations of chronic multiple sclerosis (MS)are due in part to widespread axonal abnormalities that affect lesional and nonlesional areas in the central nervous system. Wedescribe an association between microglial activation and axon/oligodendrocyte pathology at nodal and paranodal domains in normal-appearing white matter (NAWM) of MS cases and in experimental autoimmune encephalomyelitis (EAE). The extent ofparanodal axoglial (neurofascin-155/Caspr1) disruption correlated with local microglial inflammation and axonal injury (expression of nonphosphorylated neurofilaments) in MS NAWM. These changes were independent of demyelinating lesions and did not correlate with the density of infiltrating lymphocytes. Similar axoglial alterations were seen in the subcortical white matter of Parkinson disease cases and in preclinical EAE, at a time point when there is microglial activation before the infiltration of immune cells. Disruption of the axoglial unit in adjuvant-immunized animals was reversible and coincided with the resolution of microglial inflammation; paranodal damage and microglial inflammation persisted in chronic EAE. Axoglial integrity could be preserved by the administration of minocycline, which inhibited microglial activation, in actively immunized animals. These data indicate that, in MS NAWM, permanent disruption to axoglial domains in an environment of microglial inflammation is an early indicator of axonal injury that likely affects nerve conduction and may contribute to physiologic dysfunction.

Autoimmune nodopathy (AN) is a new entity in the field of peripheral neuropathies and is defined by the presence of auto-antibodies against structures of the node of Ranvier combined with specific clinico-pathophysiological features and therapy response in affected patients. The target-specific antibodies do not only serve as diagnostic biomarkers but also for treatment evaluation during follow-up. We report a 66-year-old female patient with various autoimmune diseases, including a history of membranous glomerulonephritis which presented with acute-onset, sensorimotor tetraparesis, cranial nerve involvement, and mild respiratory insufficiency. Under the suspicion of Guillain-Barré syndrome, she received intravenous immunoglobulins (IVIg) and achieved remission. At 8 months later, she relapsed with now a poor response to IVIg and developed additional features such as severe sensory ataxia, tremor, and neuropathic pain. Anti-contactin-1 IgG2 antibodies were detected, and the diagnosis was reverted to AN. Plasma exchange and rituximab treatment led to a serological remission and corresponding significant clinical improvement, and the therapy was paused. At 2 years after symptom onset, her condition worsened again with sensorimotor symptoms and severe neuropathic pain despite seronegativity for contactin-1. However, serum binding assays to teased nerve fiber staining showed recurring antibody reactivity against paranodal structures. Caspr-1 was identified as a new target antigen via cell-based assay, and high-titer antibodies of the IgG4 subclass were confirmed via ELISA. Hence, a new cycle of plasma exchange and regular rituximab treatment was initiated, with subsequent clinical improvement and serological remission. The serum neurofilament light chain (sNFL) levels were assessed retrospectively and rose and fell together with the antibody titer. This case demonstrates that autoimmunity to (para)nodal structures can reoccur especially in patients prone to autoimmune disorders and can switch its target antigen and subclass in the course of disease. The presence of auto-antibodies against different targets at the node of Ranvier has direct implications for therapeutic management. We suggest a close follow-up of patients with AN after successful therapy. In case of deterioration despite seronegativity, non-specific tests such as teased fiber assays and repeated screening for different target antigens should be considered.

Background Following partial injury to the central nervous system, cells beyond the initial injury site undergo secondary degeneration, exacerbating loss of neurons, compact myelin and function. Changes in Ca 2+ flux are associated with metabolic and structural changes, but it is not yet clear how flux through specific ion channels contributes to the various pathologies. Here, partial optic nerve transection in adult female rats was used to model secondary degeneration. Treatment with combinations of three ion channel inhibitors was used as a tool to investigate which elements of oxidative and structural damage related to long term functional outcomes. The inhibitors employed were the voltage gated Ca 2+ channel inhibitor Lomerizine (Lom), the Ca 2+ permeable AMPA receptor inhibitor YM872 and the P2X 7 receptor inhibitor oxATP. Results Following partial optic nerve transection, hyper-phosphorylation of Tau and acetylated tubulin immunoreactivity were increased, and Nogo-A immunoreactivity was decreased, indicating that axonal changes occurred acutely. All combinations of ion channel inhibitors reduced hyper-phosphorylation of Tau and increased Nogo-A immunoreactivity at day 3 after injury. However, only Lom/oxATP or all three inhibitors in combination significantly reduced acetylated tubulin immunoreactivity. Most combinations of ion channel inhibitors were effective in restoring the lengths of the paranode and the paranodal gap, indicative of the length of the node of Ranvier, following injury. However, only all three inhibitors in combination restored to normal Ankyrin G length at the node of Ranvier. Similarly, HNE immunoreactivity and loss of oligodendrocyte precursor cells were only limited by treatment with all three ion channel inhibitors in combination. Conclusions Data indicate that inhibiting any of a range of ion channels preserves certain elements of axon and node structure and limits some oxidative damage following injury, whereas ionic flux through all three channels must be inhibited to prevent lipid peroxidation and preserve Ankyrin G distribution and OPCs.