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Journal of Clinical Immunology Jul 2014Multifocal motor neuropathy affects myelinated motor axons in limb nerves at multifocal sites. It is characterized by weakness and muscle atrophy, motor conduction... (Review)
Review
Multifocal motor neuropathy affects myelinated motor axons in limb nerves at multifocal sites. It is characterized by weakness and muscle atrophy, motor conduction block, and antibodies against ganglioside GM1 which is expressed on the axolemma of nodes of Ranvier and perinodal Schwann cells. Treatment by regular IVIg courses results in temporary improvement but cannot prevent slowly progressing weakness due to axonal degeneration. This review discusses possible mechanisms of conduction block and the reasons why motor axons are selectively affected in this disorder.
Topics: Animals; Autoantibodies; Axons; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Immunotherapy; Motor Neurons; Neural Conduction; Polyneuropathies; Ranvier's Nodes; Treatment Outcome
PubMed: 24801202
DOI: 10.1007/s10875-014-0023-6 -
The Journal of Neuroscience : the... Apr 2014Clustering of Na(+) channels at the nodes of Ranvier is coordinated by myelinating glia. In the peripheral nervous system, axoglial contact at the nodes is mediated by...
Clustering of Na(+) channels at the nodes of Ranvier is coordinated by myelinating glia. In the peripheral nervous system, axoglial contact at the nodes is mediated by the binding of gliomedin and glial NrCAM to axonal neurofascin 186 (NF186). This interaction is crucial for the initial clustering of Na(+) channels at heminodes. As a result, it is not clear whether continued axon-glial contact at nodes of Ranvier is required to maintain these channels at the nodal axolemma. Here, we report that, in contrast to mice that lack either gliomedin or NrCAM, absence of both molecules (and hence the glial clustering signal) resulted in a gradual loss of Na(+) channels and other axonal components from the nodes, the formation of binary nodes, and dysregulation of nodal gap length. Therefore, these mice exhibit neurological abnormalities and slower nerve conduction. Disintegration of the nodes occurred in an orderly manner, starting with the disappearance of neurofascin 186, followed by the loss of Na(+) channels and ankyrin G, and then βIV spectrin, a sequence that reflects the assembly of nodes during development. Finally, the absence of gliomedin and NrCAM led to the invasion of the outermost layer of the Schwann cell membrane beyond the nodal area and the formation of paranodal-like junctions at the nodal gap. Our results reveal that axon-glial contact mediated by gliomedin, NrCAM, and NF186 not only plays a role in Na(+) channel clustering during development, but also contributes to the long-term maintenance of Na(+) channels at nodes of Ranvier.
Topics: Action Potentials; Animals; Ankyrins; Cell Adhesion Molecules; Cell Adhesion Molecules, Neuronal; Cell Membrane; Female; Gene Deletion; Male; Mice; Nerve Growth Factors; Neuroglia; Protein Transport; Ranvier's Nodes; Spectrin; Voltage-Gated Sodium Channels
PubMed: 24719088
DOI: 10.1523/JNEUROSCI.4752-13.2014 -
The Journal of Physiology Jul 2014The local anaesthetic lidocaine is known to block voltage-gated Na(+) channels (VGSCs), although at high concentration it was also reported to block other ion channel...
The local anaesthetic lidocaine is known to block voltage-gated Na(+) channels (VGSCs), although at high concentration it was also reported to block other ion channel currents as well as to alter lipid membranes. The aim of this study was to investigate whether the clinical regional anaesthetic action of lidocaine could be accounted for solely by the block of VGSCs or whether other mechanisms are also relevant. We tested the recovery of motor axon conduction and multiple measures of excitability by 'threshold-tracking' after ultrasound-guided distal median nerve regional anaesthesia in 13 healthy volunteers. Lidocaine caused rapid complete motor axon conduction block localized at the wrist. Within 3 h, the force of the abductor pollicis brevis muscle and median motor nerve conduction studies returned to normal. In contrast, the excitability of the motor axons at the wrist remained markedly impaired as indicated by a 7-fold shift of the stimulus-response curves to higher currents with partial recovery by 6 h and full recovery by 24 h. The strength-duration properties were abnormal with markedly increased rheobase and reduced strength-duration time constant. The changes in threshold during electrotonus, especially during depolarization, were markedly reduced. The recovery cycle showed increased refractoriness and reduced superexcitability. The excitability changes were only partly similar to those previously observed after poisoning with the VGSC blocker tetrodotoxin. Assuming an unaltered ion-channel gating, modelling indicated that, apart from up to a 4-fold reduction in the number of functioning VGSCs, lidocaine also caused a decrease of passive membrane resistance and an increase of capacitance. Our data suggest that the lidocaine effects, even at clinical 'sub-blocking' concentrations, could reflect, at least in part, a reversible structural impairment of the axolemma.
Topics: Adult; Anesthesia, Local; Anesthetics, Local; Axons; Cell Membrane; Female; Humans; Lidocaine; Male; Models, Neurological; Motor Neurons; Muscle, Skeletal; Neural Conduction; Voltage-Gated Sodium Channel Blockers
PubMed: 24710060
DOI: 10.1113/jphysiol.2014.270827 -
Journal of Neurotrauma Jul 2014The initial pathological changes of diffuse axonal injury following traumatic brain injury (TBI) include membrane disruption and loss of ionic homeostasis, which further...
The initial pathological changes of diffuse axonal injury following traumatic brain injury (TBI) include membrane disruption and loss of ionic homeostasis, which further lead to dysfunction of axonal conduction and axon disconnection. Resealing the axolemma is therefore a potential therapeutic strategy for the early treatment of TBI. Monomethoxy poly (ethylene glycol)-poly (D, L-lactic acid) di-block copolymer micelles (mPEG-PDLLA) have been shown to restore depressed compound action potentials (CAPs) of spinal axons and promote functional recovery after spinal cord injury. Here, we evaluate the effect of the micelles on repairing the injured cortical axons following TBI. Adult mice subjected to controlled cortical impact (CCI) were treated with intravenous injection of the micelles at 0 h or 4 h after injury. Evoked CAPs were recorded from the corpus callosum of coronal cortical slices at 2 days after injury. The CCI caused significant decreases in the amplitudes of two CAP peaks that were respectively generated by the faster myelinated axons and slower unmyelinated axons. Micelle treatment at both 0 h and 4 h after CCI resulted in significant increases in both CAP peak amplitudes. Injection of fluorescent dye-labeled micelles revealed high fluorescent staining in cortical gray and white matters underneath the impact site. Labeling membrane-perforated neurons by injecting a membrane impermeable dye Texas Red-labeled dextran into lateral ventricles at 2 h post-CCI revealed that immediate micelle injection after CCI did not reduce the number of dye-stained cortical neurons and dentate granule cells of the hippocampus, indicating its ineffectiveness in repairing plasma membrane of neuronal somata. We conclude that intravenous administration of mPEG-PDLLA micelles immediately or at 4 h after TBI allows brain penetration via the compromised blood brain-barrier, and thereby improves the function of both myelinated and unmyelinated axons of the corpus callosum.
Topics: Action Potentials; Animals; Axons; Brain Injuries; Corpus Callosum; Male; Mice; Micelles; Polyesters; Polyethylene Glycols; Treatment Outcome
PubMed: 24579802
DOI: 10.1089/neu.2013.3147 -
The Neuroscientist : a Review Journal... Dec 2013Myelinated nerve fibers have evolved to optimize signal propagation. Each myelin segment is attached to the axon by the unique paranodal axoglial junction (PNJ), a... (Review)
Review
Myelinated nerve fibers have evolved to optimize signal propagation. Each myelin segment is attached to the axon by the unique paranodal axoglial junction (PNJ), a highly complex structure that serves to define axonal ion channel domains and to direct nodal action currents through adjacent nodes. Surprisingly, this junction does not entirely seal the paranodal myelin sheath to the axon and thus does not entirely isolate the perinodal space from the internodal periaxonal space. Rather the paranode is penetrated by extracellular pathways between the myelin sheath and the axolemma for movement of molecules and the flow of current to and from the internodal axon. This review summarizes past and current studies demonstrating these pathways and considers what functional roles they subserve. In addition, modern genetic engineering methods permit modification of individual PNJ constituents, which provides an opportunity to define their specific functions. One component in particular, the transverse bands, plays a key role in maintaining the structure and function of the PNJ. Loss of transverse bands results not in frank demyelination but rather in subtle dysmyelination, which causes significant functional impairment. The consequences of such subtle defects in the PNJ are considered along with the relevance of these studies to human diseases of myelin.
Topics: Animals; Axons; Humans; Mice; Nerve Fibers, Myelinated; Neuroglia; Ranvier's Nodes
PubMed: 24122820
DOI: 10.1177/1073858413504627 -
Handbook of Clinical Neurology 2013A peripheral nerve trunk is composed of nerve fascicles supported in a fibrous collagenous sheath and defined by concentric layers of cells (the perineurium) that... (Review)
Review
A peripheral nerve trunk is composed of nerve fascicles supported in a fibrous collagenous sheath and defined by concentric layers of cells (the perineurium) that separate the contents (the endoneurium) from its fibrous collagen support (the epineurium). In the endoneurium are myelinated and unmyelinated fibers that are axons combined with their supporting Schwann cells to provide physical and electrical connections with end-organs such as muscle fibers and sensory endings. Axons are tubular neuronal extensions with a cytoskeleton of neurotubules and tubulin along which organelles and proteins can travel between the neuronal cell body and the axon terminal. During development some axons enlarge and are covered by a chain of Schwann cells each associated with just one axon. As the axons grow in diameter, the Schwann cells wrap round them to produce a myelin sheath. This consists of many layers of compacted Schwann cell membrane plus some additional proteins. Adjacent myelin segments connect at highly specialized structures, the nodes of Ranvier. Myelin insulates the axon so that the nerve impulse can jump from one node to the next. The region adjacent to the node, the paranodal segment, is the site of myelin terminations on the axolemma. There are connections here between the Schwann cell and the axon via a complex chain of proteins. The Schwann cell cytoplasm in the adjacent segment, the juxtaparanode, contains most of the Schwann cell mitochondria. In addition to the node, continuity of myelin lamellae is broken at intervals along the internode by helical regions of decompaction known as Schmidt-Lanterman incisures; these are seen as paler conical segments in suitably stained microscopical preparations and provide a pathway between the adaxonal and abaxonal cytoplasm. Smaller axons without a myelin sheath conduct very much more slowly and have a more complex relationship with their supporting Schwann cells that has important implications for repair.
Topics: Animals; Axons; Humans; Microscopy; Nerve Fibers; Peripheral Nerves
PubMed: 23931772
DOI: 10.1016/B978-0-444-52902-2.00002-3 -
ASN Neuro Aug 2013Dysfunction and/or disruption of nodes of Ranvier are now recognized as key contributors to the pathophysiology of various neurological diseases. One reason is that the... (Review)
Review
Dysfunction and/or disruption of nodes of Ranvier are now recognized as key contributors to the pathophysiology of various neurological diseases. One reason is that the excitable nodal axolemma contains a high density of Nav (voltage-gated Na+ channels) that are required for the rapid and efficient saltatory conduction of action potentials. Nodal physiology is disturbed by altered function, localization, and expression of voltage-gated ion channels clustered at nodes and juxtaparanodes, and by disrupted axon-glial interactions at paranodes. This paper reviews recent discoveries in molecular/cellular neuroscience, genetics, immunology, and neurology that highlight the critical roles of nodes of Ranvier in health and disease.
Topics: Animals; Autoimmune Diseases of the Nervous System; Central Nervous System; Channelopathies; Demyelinating Diseases; Humans; Ion Channels; Nerve Tissue Proteins; Nervous System Diseases; Peripheral Nervous System; Ranvier's Nodes
PubMed: 23834220
DOI: 10.1042/AN20130025 -
Current Opinion in Neurobiology Dec 2013Nodes of Ranvier are specialized axonal domains formed in response to a glial signal. Recent research advances have revealed that both CNS and PNS nodes form by several... (Review)
Review
Nodes of Ranvier are specialized axonal domains formed in response to a glial signal. Recent research advances have revealed that both CNS and PNS nodes form by several overlapping molecular mechanisms. However, the precise nature of these mechanisms and the hierarchy existing between them is considerably different in CNS versus PNS nodes. Namely, the Schwann cells of the PNS, which directly contact the nodal axolemma, secrete proteins that cluster axonodal components at the edges of the growing myelin segment. In contrast, the formation of CNS nodes, which are not contacted by the myelinating glia, is surprisingly similar to the assembly of the axon initial segment and depends largely on axonal diffusion barriers.
Topics: Animals; Humans; Neurogenesis; Neuroglia; Neurons; Ranvier's Nodes
PubMed: 23831261
DOI: 10.1016/j.conb.2013.06.003 -
Clinical Neurophysiology : Official... Oct 2013In some anti-ganglioside antibody-mediated neuropathies, human and experimental data suggest a common pathogenic mechanism of dysfunction/disruption at the node of... (Review)
Review
In some anti-ganglioside antibody-mediated neuropathies, human and experimental data suggest a common pathogenic mechanism of dysfunction/disruption at the node of Ranvier resulting in a pathophysiologic continuum from transitory nerve conduction failure to axonal degeneration. The traditional classification of polyneuropathies into demyelinating or axonal may generate some confusion in the electrophysiological diagnosis of Guillain-Barré syndrome subtypes associated with anti-ganglioside antibodies. The axonal forms show, besides axonal degeneration, promptly reversible nerve conduction failure. This may be interpreted, by a single electrophysiological study, as demyelinating conduction block or distal axonal degeneration leading to errors in classification and in establishing prognosis. Moreover the term axonal may be misleading as it is commonly associated to axonal degeneration and not to a transitory, promptly reversible, dysfunction of the excitable axolemma. To focus on the site of nerve injury and overcome the classification difficulties, we propose the new category of nodo-paranodopathy which seems appropriate to various acute and chronic neuropathies associated with anti-ganglioside antibodies and we think better systematizes the neuropathies characterized by an autoimmune attack targeting the nodal region.
Topics: Animals; Autoantibodies; Axons; Disease Models, Animal; Gangliosides; Guillain-Barre Syndrome; Humans; Neural Conduction; Polyneuropathies; Ranvier's Nodes
PubMed: 23639374
DOI: 10.1016/j.clinph.2013.03.025 -
Journal of Neuroscience Research May 2013Over a century ago, Ramon y Cajal first proposed the idea of a directionality involved in nerve conduction and neuronal communication. Decades later, it was discovered... (Review)
Review
Over a century ago, Ramon y Cajal first proposed the idea of a directionality involved in nerve conduction and neuronal communication. Decades later, it was discovered that myelin, produced by glial cells, insulated axons with periodic breaks where nodes of Ranvier (nodes) form to allow for saltatory conduction. In the peripheral nervous system (PNS), Schwann cells are the glia that can either individually myelinate the axon from one neuron or ensheath axons of many neurons. In the central nervous system (CNS), oligodendrocytes are the glia that myelinate axons from different neurons. Review of more recent studies revealed that this myelination created polarized domains adjacent to the nodes. However, the molecular mechanisms responsible for the organization of axonal domains are only now beginning to be elucidated. The molecular domains in myelinated axons include the axon initial segment (AIS), where various ion channels are clustered and action potentials are initiated; the node, where sodium channels are clustered and action potentials are propagated; the paranode, where myelin loops contact with the axolemma; the juxtaparanode (JXP), where delayed-rectifier potassium channels are clustered; and the internode, where myelin is compactly wrapped. Each domain contains a unique subset of proteins critical for the domain's function. However, the roles of these proteins in axonal domain organization are not fully understood. In this review, we highlight recent advances on the molecular nature and functions of some of the components of each axonal domain and their roles in axonal domain organization and maintenance for proper neuronal communication.
Topics: Animals; Axonal Transport; Axons; Membrane Lipids; Myelin Proteins; Myelin Sheath; Nervous System; Neuroglia; Neurons; Ranvier's Nodes
PubMed: 23404451
DOI: 10.1002/jnr.23197