Nodes Of Ranvier Research Articles

Collaborative studies of U.S.-China neurologists on acute motor axonal neuropathy.

Collaborative studies of U.S.-China neurologists on acute motor axonal neuropathy.

Insights into myelin dysfunction in schizophrenia and bipolar disorder.

Schizophrenia and bipolar disorder are disabling psychiatric disorders with a worldwide prevalence of approximately 1%. Both disorders present chronic and deteriorating prognoses that impose a large burden, not only on patients but also on society and health systems. These mental illnesses share several clinical and neurobiological traits; of these traits, oligodendroglial dysfunction and alterations to white matter (WM) tracts could underlie the disconnection between brain regions related to their symptomatic domains. WM is mainly composed of heavily myelinated axons and glial cells. Myelin internodes are discrete axon-wrapping membrane sheaths formed by oligodendrocyte processes. Myelin ensheathment allows fast and efficient conduction of nerve impulses through the nodes of Ranvier, improving the overall function of neuronal circuits. Rapid and precisely synchronized nerve impulse conduction through fibers that connect distant brain structures is crucial for higher-level functions, such as cognition, memory, mood, and language. Several cellular and subcellular anomalies related to myelin and oligodendrocytes have been found in postmortem samples from patients with schizophrenia or bipolar disorder, and neuroimaging techniques have revealed consistent alterations at the macroscale connectomic level in both disorders. In this work, evidence regarding these multilevel alterations in oligodendrocytes and myelinated tracts is discussed, and the involvement of proteins in key functions of the oligodendroglial lineage, such as oligodendrogenesis and myelination, is highlighted. The molecular components of the axo-myelin unit could be important targets for novel therapeutic approaches to schizophrenia and bipolar disorder.

Nodopathies: A distinct pathophysiological and clinical entity

Abstract
 In recent years, antibodies directed against the proteins located at the node of Ranvier have been identified in patients with immune mediated neuropathies. In this article, we review the structure of node of Ranvier and pathology associated with these antibody mediated neuropathies. We summarize the emerging concept of nodopathy/ paranodopathy, its clinical relevance and treatment implications.

Modeling ion channel clustering using critical phenomena

Recent superresolution microscopy experiments have shown that, even in unmyelinated axons, voltage gated channels are clustered together in a fashion that resembles the organization at the nodes of Ranvier. While it is known that localization of channels can be beneficial for increasing propagation speed and efficiency of action potentials, the mechanism underlying this clustering phenomenon is currently unclear. Here we investigate the role of lipid membrane phase separation and critical Casimir forces as microscopic determinants of pattern formation in cell membranes.

High-throughput functional analysis of human Nav1.6 variants expressed in adult and neonatal isoforms

SCN8A encodes the voltage-gated sodium channel NaV1.6 expressed at axon initial segments and nodes of Ranvier in central and peripheral neurons. SCN8A variants are associated with epileptic encephalopathy and related neurodevelopmental disorders. Similar to other NaV channels, SCN8A undergoes developmentally-regulated alternative mRNA splicing. Because splice isoforms of other NaV channels exhibit distinct functional properties, the SCN8A isoform used for variant expression may affect observed pathogenicity.

Clusters of neuronal neurofascin prefigure the position of a subset of nodes of Ranvier along individual central nervous system axons invivo.

SummaryThe spacing of nodes of Ranvier crucially affects conduction properties along myelinated axons. It is assumed that node position is primarily driven by growing myelin sheaths. Here, we reveal an additional mechanism of node positioning that is driven by the axon. Through longitudinal live imaging of node formation dynamics in the zebrafish central nervous system, we show that stable clusters of the cell adhesion molecule neurofascin a can accumulate at specific sites along axons prior to myelination. While some of these clusters are pushed into future node position by extending myelin sheaths, others are not and thus prefigure the position of where a mature node forms. Animals that lack full-length neurofascin a show increased internodal distances and less regular nodal spacing along single axons. Together, our data reveal the existence of an axonal mechanism to position nodes of Ranvier that does not depend on regulation by myelin sheath growth.

Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity

Cell adhesion molecules are membrane-bound proteins predominantly expressed in the central nervous system along principal axonal pathways with key roles in nervous system development, neural cell differentiation and migration, axonal growth and guidance, myelination, and synapse formation. Here, we describe ten affected individuals with bi-allelic variants in the neuronal cell adhesion molecule NRCAM that lead to a neurodevelopmental syndrome of varying severity; the individuals are from eight families. This syndrome is characterized by developmental delay/intellectual disability, hypotonia, peripheral neuropathy, and/or spasticity. Computational analyses of NRCAM variants, many of which cluster in the third fibronectin type III (Fn-III) domain, strongly suggest a deleterious effect on NRCAM structure and function, including possible disruption of its interactions with other proteins. These findings are corroborated by previous invitro studies of murine Nrcam-deficient cells, revealing abnormal neurite outgrowth, synaptogenesis, and formation of nodes of Ranvier on myelinated axons. Our studies on zebrafish nrcamaΔ mutants lacking the third Fn-III domain revealed that mutant larvae displayed significantly altered swimming behavior compared to wild-type larvae (p < 0.03). Moreover, nrcamaΔ mutants displayed a trend toward increased amounts of α-tubulin fibers in the dorsal telencephalon, demonstrating an alteration in white matter tracts and projections. Taken together, our study provides evidence that NRCAM disruption causes a variable form of a neurodevelopmental disorder and broadens the knowledge on the growing role of the cell adhesion molecule family in the nervous system.

Diffuse Traumatic Injury in the Mouse Disrupts Axon-Myelin Integrity in the Cerebellum.

Cerebellar dysfunction after traumatic brain injury (TBI) is commonly suspected based on clinical symptoms, although cerebellar pathology has rarely been investigated. To address the hypothesis that the cerebellar axon-myelin unit is altered by diffuse TBI, we used the central fluid percussion injury (cFPI) model in adult mice to create widespread axonal injury by delivering the impact to the forebrain. We specifically focused on changes in myelin components (myelin basic protein [MBP], 2',3'-cyclic nucleotide 3'-phosphodiesterase [CNPase], nodal/paranodal domains [neurofascin (Nfasc), ankyrin-G], and phosphorylated neurofilaments [SMI-31, SMI-312]) in the cerebellum, remote from the impact, at two, seven, and 30 days post-injury (dpi). When compared with sham-injured controls, cerebellar MBP and CNPase protein levels were decreased at 2 dpi that remained reduced up to 30 dpi. Diffuse TBI induced different effects on neuronal (Nfasc 186, Nfasc 140) and glial (Nfasc 155) neurofascin isoforms that play a key role in the assembly of the nodes of Ranvier. Expression of Nfasc 140 in the cerebellum increased at 7 dpi, in contrast to Nfasc 155 levels, which were decreased. Although neurofascin binding partner ankyrin-G protein levels decreased acutely after cFPI, its expression levels increased at 7 dpi and remained unchanged up to 30 dpi. The TBI-induced reduction in neurofilament phosphorylation (SMI-31) observed in the cerebellum was closely associated with decreased levels of the myelin proteins MBP and CNPase. This is the first evidence of temporal and spatial structural changes in the axon-myelin unit in the cerebellum, remote from the location of the impact site, in a diffuse TBI model in mice.

Excitable Axonal Domains Adapt to Sensory Deprivation in the Olfactory System

The axon initial segment (AIS), nodes of Ranvier, and the oligodendrocyte-derived myelin sheath have significant influence on the firing patterns of neurons and the faithful, coordinated transmission of action potentials (APs) to downstream brain regions. In the olfactory bulb (OB), olfactory discrimination tasks lead to adaptive changes in cell firing patterns, and the output signals must reliably travel large distances to other brain regions along highly myelinated tracts. Whether myelinated axons adapt to facilitate olfactory sensory processing is unknown. Here, we investigate the morphology and physiology of mitral cell (MC) axons in the olfactory system of adult male and female mice and show that unilateral sensory deprivation causes system-wide adaptations in axonal morphology and myelin thickness. MC spiking patterns and APs also adapted to sensory deprivation. Strikingly, myelination and MC physiology were altered on both the deprived and nondeprived sides, indicating system level adaptations to reduced sensory input. Our work demonstrates a previously unstudied mechanism of plasticity in the olfactory system.SIGNIFICANCE STATEMENTSuccessful transmission of information from the olfactory bulb (OB) to piriform cortex through the lateral olfactory tract (LOT) relies on synchronized arrival of action potentials (APs). The coincident arrival of APs is dependent on reliable generation of APs in the axon initial segment (AIS) and fast conduction mediated by axon myelination. Here, we studied changes in mitral cell (MC) firing and AIS structure as well as changes in myelination of the LOT on unilateral olfactory deprivation in the adult mouse. Strikingly, myelination and MC physiology were altered on both the deprived and nondeprived sides, indicating system level adaptations to reduced sensory input. Our work demonstrates a previously unstudied mechanism of plasticity in the olfactory system.

Mind the gap: Nodes of Ranvier are remodeled by chronic psychosocial stress and neuronal activity

Mind the gap: Nodes of Ranvier are remodeled by chronic psychosocial stress and neuronal activity

Two distinct types of nodes of Ranvier support auditory nerve function in the mouse cochlea.

The auditory nerve (AN) of the inner ear is the primary conveyor of acoustic information from sensory hair cells to the brainstem. Approximately 95% of peripheral AN fibers are myelinated by glial cells. The integrity of myelin and the glial-associated paranodal structures at the node of Ranvier is critical for normal AN activity and axonal survival and function in the central auditory nervous system. However, little is known about the node of Ranvier's spatiotemporal development in the AN, how the aging process (or injury) affects the activity of myelinating glial cells, and how downstream alterations in myelin and paranodal structure contribute to AN degeneration and sensorineural hearing loss. Here, we characterized two types of Ranvier nodes-the axonal node and the ganglion node-in the mouse peripheral AN, and found that they are distinct in several features of postnatal myelination and age-related degeneration. Cellular, molecular, and structure-function correlations revealed that the two node types are each critical for different aspects of peripheral AN function. Neural processing speed and synchrony is associated with the length of the axonal node, while stimulus level-dependent amplitude growth and action potentials are associated with the ganglion node. Moreover, our data indicate that dysregulation of glial cells (e.g., satellite cells) and degeneration of the ganglion node structure are an important new mechanism of age-related hearing loss.

A Perspective on the Potential of Opsins as an Integral Mechanism of Photobiomodulation: It's Not Just the Eyes.

Objective: To investigate the potential relationship between opsins and photobiomodulation. Background: Opsins and other photoreceptors occur in all phyla and are important in light-activated signaling and organism homeostasis. In addition to the visual opsin systems of the retina (OPN1 and OPN2), there are several non-visual opsins found throughout the body tissues, including encephalopsin/panopsin (OPN3), melanopsin (OPN4), and neuropsin (OPN5), as well as other structures that have light-sensitive properties, such as enzymes, ion channels, particularly those located in cell membranes, lysosomes, and neuronal structures such as the nodes of Ranvier. The influence of these structures on exposure to light, including self-generated light within the body (autofluorescence), on circadian oscillators, and circadian and ultradian rhythms have become increasingly reported. The visual and non-visual phototransduction cascade originating from opsins and other structures has potential significant mechanistic effects on tissues and health. Methods: A PubMed and Google Scholar search was made using the search terms "photobiomodulation", "light", "neuron", "opsins", "neuropsin", "melanopsin", "encephalopsin", "rhodopsin", and "chromophore". Results: This review was examined the influence of neuropsin (also known as kallikrein 8), encephalopsin, and melanopsin specifically on ion channel function, and more broadly on the central and peripheral nervous systems. The relationship between opsins 3, 4, and 5 and photobiomodulation mechanisms was evaluated, along with a proposed role of photobiomodulation through opsins and light-sensitive organelles as potential alleviators of symptoms and accelerators of beneficial regenerative processes. The potential clinical implications of this in musculoskeletal conditions, wounds, and in the symptomatic management of neurodegenerative disease was also examined. Conclusions: Systematic research into the pleotropic therapeutic role of photobiomodulation, mediated through its action on opsins and other light-sensitive organelles may assist in the future execution of safe, low-risk precision medicine for a variety of chronic and complex disease conditions, and for health maintenance in aging.

Impact of Neurofascin on Chronic Inflammatory Demyelinating Polyneuropathy via Changing the Node of Ranvier Function: A Review.

The effective conduction of action potential in the peripheral nervous system depends on the structural and functional integrity of the node of Ranvier and paranode. Neurofascin (NF) plays an important role in the conduction of action potential in a saltatory manner. Two subtypes of NF, NF186, and NF155, are involved in the structure of the node of Ranvier. In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), anti-NF antibodies are produced when immunomodulatory dysfunction occurs, which interferes with the conduction of action potential and is considered the main pathogenic factor of CIDP. In this study, we describe the assembling mechanism and anatomical structure of the node of Ranvier and the necessary cell adhesion molecules for its physiological function. The main points of this study are that we summarized the recent studies on the role of anti-NF antibodies in the changes in the node of Ranvier function and its impact on clinical manifestations and analyzed the possible mechanisms underlying the pathogenesis of CIDP.

Persistent myelin abnormalities in a third trimester-equivalent mouse model of fetal alcohol spectrum disorder.

Abnormal diffusion within white matter (WM) tracts has been linked to cognitive impairment in children with fetal alcohol spectrum disorder. Whether changes to myelin organization and structure underlie the observed abnormal diffusion patterns remains unknown. Using a third trimester-equivalent mouse model of alcohol exposure, we previously demonstrated acute loss of oligodendrocyte lineage cells with persistent loss of myelin basic protein and lower fractional anisotropy (FA) in the corpus callosum (CC). Here, we tested whether these WM deficits are accompanied by changes in: (i) axial diffusion (AD) and radial diffusion (RD), (ii) myelin ultrastructure, or (iii) structural components of the node of Ranvier. Mouse pups were exposed to alcohol or air vapor for 4h daily from postnatal day (P)3 to P15 (BEC: 160.4±12.0mg/dl; range=128.2 to 185.6mg/dl). Diffusion tensor imaging (DTI) and histological analyses were performed on brain tissue isolated at P50. Diffusion parameters were measured with Paravision™ 5.1 software (Bruker) following ex vivo scanning in a 7.0T MRI. Nodes of Ranvier were identified using high-resolution confocal imaging of immunofluorescence for Nav 1.6 (nodes) and Caspr (paranodes) and measured using Imaris™ imaging software (Bitplane). Myelin ultrastructure was evaluated by calculating the G-ratio (axonal diameter/myelinated fiber diameter) on images acquired using transmission electron microscopy. Consistent with our previous study, high resolution DTI at P50 showed lower FA in the CC of alcohol-exposed mice (p=0.0014). Here, we show that while AD (diffusion parallel to CC axons) was similar between treatment groups (p=0.30), RD (diffusion perpendicular to CC axons) in alcohol-exposed subjects was significantly higher than in controls (p=0.0087). In the posterior CC, where we identified the highest degree of abnormal diffusion, node of Ranvier length did not differ between treatment groups (p=0.41); however, the G-ratio of myelinated axons was significantly higher in alcohol-exposed animals than controls (p=0.023). High resolution DTI revealed higher RD at P50 in the CC of alcohol-exposed animals, suggesting less myelination of axons, particularly in the posterior regions. In agreement with these findings, ultrastructural analysis of myelinated axons in the posterior CC showed reduced myelin thickness in alcohol-exposed animals, evidenced by a higher G-ratio.

Astrocytes regulate action potential propagation in myelinated axons: It is very crowded at the node of Ranvier

• Astrocytes regulate action potential propagation in myelinated axons of CNS white matter. • Astrocyte-axon integration through purinergic (ATP and adenosine) signalling. • Astrocyte Ca 2+ signalling triggers their release of ATP which is converted to adenosine. • Activation of A2A receptors regulate axonal excitability through HCN channels. • Hence, astrocytes modify WM information flow and neural circuit function in pathways that regulate all facets of brain and bodily functions.

Serum Neurofilament Light Chain and Contactin-1 Levels Are Not Potential Serum Biomarkers in Anti-MAG IgM Paraprotein Related Peripheral Neuropathy

IntroductionPeripheral neuropathies (PN) caused by immunoglobulin M (IgM) paraproteinemia are rare disorders that require close collaboration between hematologists and neurologists for adequate diagnosis and management. The IgM paraproteinemia is caused by an underlying B-cell clone that can often be classified as IgM monoclonal gammopathy (IgM monoclonal gammopathy of undetermined significance (MGUS) or Waldenström macroglobulinaemia (WM)). Anti-myelin-associated glycoprotein (MAG) IgM paraprotein related PN (anti-MAG PNP) is the most frequent variety and accounts for approximately 50% of cases. Treatment targeted at the B-cell clone i.e. rituximab +/- chemotherapy, is only indicated in severe and/or progressive cases. However, establishing disease severity and tracking progression over time is difficult since the most prominent symptoms, i.e. imbalance, gait ataxia, sensory disturbances and tremor, are difficult to capture reliably. Anti-MAG titers and paraprotein levels do not correlate well with disease activity and are thus not suitable as biomarkers for disease severity, activity and/or response. The lack of reliable biomarkers also impacts successful execution of clinical trials and therefore hampers introduction of novel targeted non-cytotoxic therapies such as BTK inhibition in this patient population. Therefore, biomarkers for disease severity, activity and response to treatment represent a great unmet need in anti-MAG PN.Nerve damage proteins are increasingly used as disease-overarching response biomarkers in neuropathies, and have been introduced not only in the research setting but also in routine clinical care. Neurofilament light chain (NfL) is used as response biomarker by detecting axonal damage regardless of the underlying disorder, and, recently, contactin-1 (CNTN-1) has been identified as a potential biomarker for damage to the paranode (a nerve region in between the node of Ranvier and compact myelin) where the MAG protein is also present. We therefore aimed to assess whether serum NfL, and CNTN-1 levels may function as nerve damage biomarkers in anti-MAG PN.MethodsWe included treatment-naïve patients with anti-MAG PN (PN) who fulfilled the following criteria: IgM paraproteinemia in the serum, presence of an IgM MAG-antibody in the serum, a clinical diagnosis of anti-MAG PN by a neurologist with expertise in peripheral nerve disorders confirmed by nerve conduction studies. As controls, treatment-naïve patients with IgM MGUS or WM without signs of neuropathy were included (non-PN). NfL levels were measured in serum using a Simoa assay. Abnormal sNfL levels were defined as at or above the 95th percentile of age-specific cut-off values in healthy controls (HCs). CNTN-1 levels were measured using the Human Magnetic Luminex Assay. Abnormal sCNTN1 levels were defined as below the 5th percentile of values in HCs. Differences between PN and non-PN groups were assessed with the Mann-Whitney U test.ResultsA total of 24 PN and 10 non-PN patients were included (Table 1). In the PN cohort, all patients had anti-MAG antibodies, with a titer of >10.000 in 22 (92%) patients. Data from 222 HCs (mean age 46 years; SD 14; range 19-98 years) were used to establish reference values. Median sNfL levels were similar between PN and non-PN patients (Table 2). Abnormal sNfL levels were present in 4 (17%) PN patients (range sNfL: 29.7-42.8 pg/mL) and in 1 (10%; 59.2pg/mL) non-PN patient (Figure 1A). Median sCNTN1 levels were also similar between PN and non-PN patients (Table 2). One (4%) patient in the PN cohort and 1 (10%) patient in the non-PN cohort had abnormal CNTN-1 levels (Figure 1B).ConclusionOur results do not support further studies on NfL and/or CNTN-1 in serum as potential biomarkers in anti-MAG PN, since the majority of anti-MAG PN and non-PN patients had normal levels of sNfL and sCNTN-1. In case sNfL was abnormal, levels were only modestly increased above cutoff and substantially lower compared to the high levels seen in other neuropathies. [Display omitted] DisclosuresMinnema: Alnylam: Consultancy; Celgene: Other: Travel expenses; BMS: Consultancy; Cilag: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy. Kersten: Celgene: Research Funding; Novartis: Consultancy, Honoraria, Other: Travel support; Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; BMS/Celgene: Consultancy, Honoraria; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding. Vos: Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Travel reimbursement.

P.055 Clinical and Electrophysiological characteristics of anti-nodal/paranodal antibodies in chronic inflammatory demyelinating polyradiculoneuropathy patients

Background: CIDP is an autoimmune polyneuropathy. Antibodies against the Node of Ranvier have been described, NF155,NF140/186 and contactin-1. Methods: A retrospective review of patients with CIDP who tested positive for anti-nodal/paranodal antibodies via Western blot were evaluated. We have included 20 sero-negative CIDP patients. All patients met definite or probable EFNS criteria. clinical, electrophysiological data and response to treatment were obtained. Results: Forty-five patients tested positive for the antibodies. Sixteen were positive for NF155, 11 for NF140, 5 for CNTN1,11 were double positive for NF155 and NF140, and 3 were triple positive for NF155, NF140 and CNTN1. Age of onset was similar in both seronegative (53.9 ± 3.1 yrs.) versus seropositive (52.3 ± 2.4 yrs.). Chronic presentation manifested in 85% of seronegative, 80% of seropositive patients.Intrestingly,all triple-positive patients presented with a more acute presentation (i.e,&lt;8 wks.) 7/20 seronegative (35%),1/16 NF155, 6/11 NF140,1/5 contactin, 2/11 of double-positive, 3/3 of triple-positive (28%,13/46) responded to IVIg. Conclusions: No major clinical or electrophysiological differences between groups. triple-positive patients showed 100% response to IVIg.These results cast doubt on the specificity of the Western blot as a clinico-electrophysiologic discriminator. Future testing with cell-based assays will likely provide a robust measure that will guide treatment decision.

Developmental Temporal Patterns and Molecular Network Features in the Transcriptome of Rat Spinal Cord

The molecular network features of spinal cord development that are integral to tissue engineering remain poorly understood in placental mammals, especially in terms of their relationships with vital biological processes such as regeneration. Here, using a large-scale temporal transcriptomic analysis of rat spinal cord from the embryonic stage to adulthood, we show that fluctuating RNA expression levels reflect highly active transcriptional regulation, which may initiate spinal cord patterning. We also demonstrate that microRNAs (miRNAs) and transcriptional factors exhibit a mosaic profile based on their expression patterns, while differential alternative splicing events reveal that alternative splicing may be a driving force for the development of the node of Ranvier. Our study also supports the existence of a negative correlation between innate immunity and intrinsic growth capacity. Epigenetic modifications appear to perform their respective regulatory functions at different stages of development, while guanine nucleotide-binding protein (G protein)-coupled receptors (including olfactory receptors (ORs)) may perform pleiotropic roles in axonal growth. This study provides a valuable resource for investigating spinal cord development and complements the increasing number of single-cell datasets. These findings also provide a genetic basis for the development of novel tissue engineering strategies.

Abdominal Segmental Myoclonus Mimicking Belly Dancer Dyskinesias in CASPR2 Antibody Encephalomyelitis.

An 86-year-old man presented with continuous movements of the abdominal wall (abdominal segmental myoclonus mimicking a belly dancer), gait unsteadiness, progressive cognitive deficit, episodic symptomatic hypotension, and diaphoresis for 2 months. Clinical examination confirmed cognitive dysfunction, and showed bilateral proximal muscle weakness of the upper and lower limbs and absent deep tendon reflexes. The Video shows the presence of spontaneous rhythmic, continuous, sinuous movements involving the abdominal muscles (Video 1). MRI of the spinal cord and the brain were normal. Electroencephalography showed generalized background slowing in the absence of epileptiform discharges. Polymyographic studies revealed rhythmic (about 2 Hz) electromyography bursts with variable duration of 500 to 1000 ms present with synchronous onset in the rectus abdominis and paravertebral muscles (Fig. 1). Detailed blood analysis was normal except for the presence of contactin-associated protein-like 2 (CASPR2) antibodies (IgG ≥1:40960). Cerebrospinal fluid analyses showed the presence of oligoclonal bands and CASPR2 antibody (IgG ≥1:160). Other anti-neuronal antibodies were absent, both on blood and cerebrospinal fluid analyses. Thoraco-abdominal-pelvic CT and whole-body FDG-PET did not show thymoma or other neoplasia. A diagnosis of CASPR2 antibody-related encephalomyelitis was made. Treatment with intravenous immunoglobulin and oral corticosteroids was started. Because of the absence of clinical improvement, plasma exchange and rituximab treatment were started leading to dramatic improvement of abdominal myoclonus but moderate effect on gait unsteadiness and cognitive deficit. CASPR2 is a membrane protein expressed in the central and peripheral nervous system, with its cytoplasmic domain essential for the function of potassium channel Kv1.1 clustering at the juxtaparanodes of myelinated axons. It is involved in neuronal excitability (i.e., stabilize conduction at nodes of Ranvier, and maintain resting potential) and synaptic transmission.1 CASPR2 antibodies induce a functional blocking of the potassium channel. CASPR2 antibody–associated disorders include acquired neuromyotonia, Morvan syndrome, limbic encephalitis, seizures and cerebellar ataxia. Diagnosis of CASPR2-related nervous system disorders is based on the clinical presentation and the presence of specific autoantibodies. Based on the earlier reported cases of CASPR2-associated encephalomyelitis, cerebral and spinal MRI is unremarkable in the majority of cases.2 T2/FLAIR hyperintensities can be observed in the medial temporal lobes especially in patients with cognitive deficit and seizures, and brainstem hyperintensities or cerebellar atrophy in patients presenting with ataxia. Focal (especially in the temporal regions) or diffuse slowing and sharp waves may be observed on electroencephalography. CASPR2 antibody-related encephalomyelitis are frequently associated with other autoimmune affections (including thyroiditis or myasthenia gravis), and paraneoplastic in a minority of cases (mainly related to thymoma).2 The most striking clinical feature in our case was the presence of rhythmic abdominal myoclonus resembling belly dance. Belly dancer myoclonus is a segmental myoclonus considered to be of spinal origin involving sometimes also diaphragm muscles. Lower limb myoclonus while standing or walking has been earlier reported as a movement disorder phenotype in CASPR2 antibody-related encephalomyelitis.3, 4 One patient with spinal myoclonus has been reported with clinical lower limb myoclonus associated with abdominal myoclonus only observed by electromyography.5 To the best of our knowledge, this is the first case of clinical abdominal myoclonus associated with CASPR2 antibodies. We would like to thank Drs Anne-Laurie Pinto and Sergio Muniz-Castrillo for the analysis of CSF samples. We would like to thank Dr Sarah Coudray for the attainment and interpretation of the electrophysiological data. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique. L.K.: 1A, 2C, 3A D.R.: 2C, 3B J.H.: 1C, 2B G.C.: 1A, 2C, 3A, 3B The present work respects ethical guidelines. The authors confirm that the approval of an institutional review board was not required for this work. Written consent was obtained for showing the patients' video. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors declare that there are no funding sources or conflicts of interest relevant to this work. The authors declare that there are no additional disclosures to report.

L-Type Ca2+ Channels of NG2 Glia Determine Proliferation and NMDA Receptor-Dependent Plasticity.

NG2 (nerve/glial antigen 2) glia are uniformly distributed in the gray and white matter of the central nervous system (CNS). They are the major proliferating cells in the brain and can differentiate into oligodendrocytes. NG2 glia do not only receive synaptic input from excitatory and inhibitory neurons, but also secrete growth factors and cytokines, modulating CNS homeostasis. They express several receptors and ion channels that play a role in rapidly responding upon synaptic signals and generating fast feedback, potentially regulating their own properties. Ca2+ influx via voltage-gated Ca2+ channels (VGCCs) induces an intracellular Ca2+ rise initiating a series of cellular activities. We confirmed that NG2 glia express L-type VGCCs in the white and gray matter during CNS development, particularly in the early postnatal stage. However, the function of L-type VGCCs in NG2 glia remains elusive. Therefore, we deleted L-type VGCC subtypes Cav1.2 and Cav1.3 genes conditionally in NG2 glia by crossbreeding NG2-CreERT2 knock-in mice to floxed Cav1.2 and flexed Cav1.3 transgenic mice. Our results showed that ablation of Cav1.2 and Cav1.3 strongly inhibited the proliferation of cortical NG2 glia, while differentiation in white and gray matter was not affected. As a consequence, no difference on myelination could be detected in various brain regions. In addition, we observed morphological alterations of the nodes of Ranvier induced by VGCC-deficient NG2 glia, i.e., shortened paired paranodes in the corpus callosum. Furthermore, deletion of Cav1.2 and Cav1.3 largely eliminated N-methyl-D-aspartate (NMDA)-dependent long-term depression (LTD) and potentiation in the hippocampus while the synaptic input to NG2 glia from axons remained unaltered. We conclude that L-type VGCCs of NG2 glia are essential for cell proliferation and proper structural organization of nodes of Ranvier, but not for differentiation and myelin compaction. In addition, L-type VGCCs of NG2 glia contribute to the regulation of long-term neuronal plasticity.