Contactin-associated Protein Research Articles

The significance of anti-neuronal antibodies for acute psychiatric disorders: a retrospective case\u2013controlled study

BackgroundThe clinical significance of anti-neuronal antibodies in patients with psychiatric disorders, but without encephalitis, remains unknown. In patients admitted to acute psychiatric inpatient care we aimed to identify clinical features distinguishing anti-neuronal antibody positive patients from matched controls.ResultsPatients who were serum-positive to N-methyl d-aspartate receptor (NMDAR) (n = 21), contactin-associated protein 2 (CASPR2) (n = 14) and/or glutamic acid decarboxylase 65 (GAD65) (n = 9) antibodies (cases) were age and sex matched (1:2) with serum-negative patients from the same cohort (controls). The prevalence and severity of psychiatric symptoms frequently encountered in NMDAR, CASPR2 and GAD65 antibody associated disorders were compared in cases and controls. NMDAR, CASPR2 and GAD65 antibody positive patients did not differ in their clinical presentation from matched serum negative controls.ConclusionIn this cohort, patients with and without NMDAR, CASPR2 and GAD65 antibodies admitted to acute psychiatric inpatient care had similar psychiatric phenotypes. This does not exclude their clinical relevance in subgroups of patients, and studies further investigating the clinical significance of anti-neuronal antibodies in patients with psychiatric symptomatology are needed.

Association of Leucine-Rich Glioma Inactivated Protein 1, Contactin-Associated Protein 2, and Contactin 2 Antibodies With Clinical Features and Patient-Reported Pain in Acquired Neuromyotonia

Although acquired autoimmune neuromyotonia (NMT) is associated with voltage-gated potassium channel (VGKC)-complex antibodies, to date there has been no systematic study of autoantibodies to the specific antigens leucine-rich glioma inactivated protein 1 (LGI1), contactin-associated protein 2 (CASPR2), and contactin 2 together with the full clinical syndrome, particularly pain and autonomic and central nervous system involvement. To study the full spectrum of clinical features and serum autoantibodies in patients with NMT, including the effects of pain on quality of life. A cohort study of clinical features and serologic testing in 38 patients with electrophysiologically-confirmed NMT, reviewed clinically between February 2007 and August 2009, in the Universities of Sydney and Kagoshima and followed up across 2 to 4 years. Association of NMT with quality of life was researched in an independent, patient-led, online pain survey conducted from April 2012 to May 2012. Serologic analyses were performed in 2012, and final data analysis was performed in 2016. Clinical data and scores on the modified Rankin Scale (mRS), which measures disability on a range of 0 to 6, with 0 indicating normal and 6 indicating death, before and after treatments were combined with CASPR2, LGI1, and contactin 2 antibody status. Among the 38-person NMT cohort, 25 (65.8%) were male and the median (range) age was 55 (12-85) years. Twenty-three (60.5%) were Japanese and 15 (39.5%) were of white race/ethnicity. Symptomatic treatments (mainly antiepileptic drugs) were used in most patients with mild disease (12 patients with mRS <3), whereas immunotherapies were successful in most patients with mRS scores greater than 2. Autoantibodies to VGKC-complex antigens (17 patients [45%]), bound to CASPR2 (5 [13%]), contactin 2 (5 patients, 1 with CASPR2 [13%]), LGI1 (2 [5%]), or both LGI1 and CASPR2 (6 [16%]). The last group of 6 patients had high mRS scores (mean [SD], 3.8 [1.7]), thymoma (4 patients), pain (5 patients), autonomic (6 patients) and sleep (5 patients) disturbance, suggesting Morvan syndrome. The 56 responders to the independent patient-led survey reported pain that could be severe, anatomically widespread, and that often resulted in unemployment, domestic problems, and poor quality of life. The cohort study detailed underrecognized aspects of the clinical and serologic spectrum of NMT. The heterogeneity of clinical features and of specific antibodies limit associations, but the common existence of thymoma, pain, and autonomic and central nervous system features, often with both LGI1 and CASPR2 antibodies, should be better recognized to more completely address the range of comorbidities and consequences of the disease regarding quality of life.

Metabotropic glutamate type 5 receptor requires contactin-associated protein 1 to control memory formation.

The hippocampus is a key brain region for memory formation. Metabotropic glutamate type 5 receptors (mGlu5R) are strongly expressed in CA1 pyramidal neurons and fine-tune synaptic plasticity. Accordingly, mGlu5R pharmacological manipulation may represent an attractive therapeutic strategy to manage hippocampal-related neurological disorders. Here, by means of a membrane yeast two-hybrid screening, we identified contactin-associated protein 1 (Caspr1), a type I transmembrane protein member of the neurexin family, as a new mGlu5R partner. We report that mGlu5R and Caspr1 co-distribute and co-assemble both in heterologous expression systems and in rat brain. Furthermore, downregulation of Caspr1 in rat hippocampal primary cultures decreased mGlu5R-mediated signaling. Finally, silencing Caspr1 expression in the hippocampus impaired the impact of mGlu5R on spatial memory. Our results indicate that Caspr1 plays a pivotal role controlling mGlu5R function in hippocampus-dependent memory formation. Hence, this new protein-protein interaction may represent novel target for neurological disorders affecting hippocampal glutamatergic neurotransmission.

Morvan's syndrome-is a pathogen behind the curtain?

Morvan's syndrome is a rare syndrome of likely autoimmune etiology characterized by peripheral nerve hyperexcitability, dysautonomia, insomnia, and fluctuating delirium with prominent hallucinations. Since its first mention in 1890, less than 100 cases have been described in literature. The largest existing review includes details of 29 cases. This case series describes 4 cases (M = 4) of Morvan's syndrome which presented between May and November 2017 to a single tertiary care referral teaching hospital in north India. All the four patients manifested behavioral abnormalities, sleep disturbances, hallucinations, autonomic dysfunction, and clinical signs of peripheral nerve hyperexcitability, mostly as myokymia. Two of the patients had Anti-CASPR2 (contactin-associated protein 2) antibodies. Three of them had electromyography features of peripheral nerve hyperexcitability and only one had elevated cerebrospinal fluid protein level. We hypothesize that Morvan's syndrome and other less characterized autoimmune encephalitis/peripheral nervous system syndromes may have infectious triggers. A possible viral trigger may result in generation of autoantibodies which result in the typical manifestations. We base these hypotheses on the finding of four cases of an orphan disease within a short period of time in a limited geographical distribution.

Distinct HLA associations of LGI1 and CASPR2-antibody diseases.

The recent biochemical distinction between antibodies against leucine-rich, glioma-inactivated-1 (LGI1), contactin-associated protein-2 (CASPR2) and intracellular epitopes of voltage-gated potassium-channels (VGKCs) demands aetiological explanations. Given established associations between human leucocyte antigen (HLA) alleles and adverse drug reactions, and our clinical observation of frequent adverse drugs reactions in patients with LGI1 antibodies, we compared HLA alleles between healthy controls (n = 5553) and 111 Caucasian patients with VGKC-complex autoantibodies. In patients with LGI1 antibodies (n = 68), HLA-DRB1*07:01 was strongly represented [odds ratio = 27.6 (95% confidence interval 12.9-72.2), P = 4.1 × 10-26]. In contrast, patients with CASPR2 antibodies (n = 31) showed over-representation of HLA-DRB1*11:01 [odds ratio = 9.4 (95% confidence interval 4.6-19.3), P = 5.7 × 10-6]. Other allelic associations for patients with LGI1 antibodies reflected linkage, and significant haplotypic associations included HLA-DRB1*07:01-DQA1*02:01-DQB1*02:02, by comparison to DRB1*11:01-DQA1*05:01-DQB1*03:01 in CASPR2-antibody patients. Conditional analysis in LGI1-antibody patients resolved further independent class I and II associations. By comparison, patients with both LGI1 and CASPR2 antibodies (n = 3) carried yet another complement of HLA variants, and patients with intracellular VGKC antibodies (n = 9) lacked significant HLA associations. Within LGI1- or CASPR2-antibody patients, HLA associations did not correlate with clinical features. In silico predictions identified unique CASPR2- and LGI1-derived peptides potentially presented by the respective over-represented HLA molecules. These highly significant HLA associations dichotomize the underlying immunology in patients with LGI1 or CASPR2 antibodies, and inform T cell specificities and cellular interactions at disease initiation.10.1093/brain/awy109_video1awy109media15796480660001.

Autoantibodies Against the Node of Ranvier in Seropositive Chronic Inflammatory Demyelinating Polyneuropathy: Diagnostic, Pathogenic, and Therapeutic Relevance.

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.

Current Perspective on Voltage-gated Potassium Channel Complex Antibody Associated Diseases

Voltage-gated potassium channel (VGKC) complex auto-antibodies were initially identified in Isaacs' syndrome (IS), which is characterized by muscle cramps and neuromyotonia. These antibodies were subsequently identified in patients with Morvan's syndrome (MoS), which includes IS in conjunction with psychosis, insomnia, and dysautonomia. The antibodies have also been detected in a patient with limbic encephalopathy (LE) presenting with prominent amnesia and frequent seizures. Typical cases of LE have adult-onset, with frequent, brief dystonic seizures that predominantly affect the arms and ipsilateral face, and has recently been termed faciobrachial dystonic seizures. Autoantibodies against the extracellular domains of VGKC complex proteins, leucine-rich glioma-inactivated 1 (LGI1), and contactin-associated protein-2 (Caspr2), occur in patients with IS, MoS, and LE. However, routine testing has detected VGKC complex antibodies without LGI1 or Caspr2 reactivities (double-negative) in patients with other diseases, such as Creutzfeldt-Jakob disease and amyotrophic lateral sclerosis. Furthermore, double-negative VGKC complex antibodies are often directed against cytosolic epitopes of Kv1 subunits. Therefore, these antibodies should no longer be classified as neuronal-surface antibodies and lacking pathogenic potential. Novel information has been generated regarding autoantibody disruption of the physiological functions of target proteins. LGI1 antibodies neutralize the interaction between LGI1 and ADAM22, thereby reducing the synaptic AMPA receptors. It may be that the main action is on inhibitory neurons, explaining why the loss of AMPA receptors causes amnesia, neuronal excitability and seizures.

Changes in the axo-glial junctions of the optic nerves of cuprizone-treated mice

Demyelination induced by cuprizone in mice has served a useful model system for the study of demyelinating diseases, such as multiple sclerosis. Severity of demyelination by cuprizone, however, varies across different regions of the central nervous system; the corpus callosum is sensitive, while the optic nerves are resistant. Here, we investigated the effects of cuprizone on optic nerves, focusing on the axo-glial junctions. Immunostaining for sodium channels, contactin-associated protein, neurofascins, and potassium channels revealed that there were no massive changes in the density and morphology of the axo-glial junctions in cuprizone-treated optic nerves. However, when we counted the number of incomplete junctional complexes, we observed increased numbers of isolated paranodes. These isolated paranodes were immunopositive for both axonal and glial membrane proteins, indicating that they were the contact sites between axons and glia. These were not associated with sodium channels or potassium channels, suggesting the absence of physiological functions. When teased axons from cuprizone-treated optic nerves were immunostained, the isolated paranodes were found at the internode region of the myelin. From these observations, we conclude that cuprizone induces new contacts between axons and myelins at the internode region.

RNA sequencing and differential expression reveals the effects of serial oestrus synchronisation on ovarian genes in dairy goats.

A total of 24 female Xinong Saanen dairy goats were used to examine differentially expressed genes (DEGs) in the ovaries of goats treated once or three times for oestrus synchronisation (ES). The goats were randomly divided into two groups: one group received three ES treatments at fortnightly intervals (repeated or triple ES group), whereas the other was only treated once on the same day as the third ES treatment for the triple group (control group) during the breeding season. Ovaries of three goats in oestrus from each group were collected for morphological examination and transcriptome sequencing, while the rest of the goats were artificially inseminated twice. Litter size and fecundity rate tended (P=0.06) to be lower in the triple ES group. A total of 319 DEGs were identified, including carbohydrate sulphotransferase 8 (CHST8), corticosteroid-binding globulin (CBG), oestradiol 17-β-dehydrogenase 1 (DHB1), oestrogen receptor 1 (ESR1), progestin and adipoQ receptor family member 4 (PAQR4), PAQR9, prostacyclin synthase (PTGIS), contactin-associated protein (CNTNAP4), matrix metalloproteinase-2 (MMP-2), regulator of G-protein signalling 9-2 (RGS9-2) and sperm surface protein Sp17 (Sp17); these were the most promising novel candidate genes for reproductive performances in goats. Our study indicates that triple ES could cause DNA damage and alter gene expression in goat ovaries, potentially affecting ovary function, neural regulation and hormone secretion.

Antibody-mediated central nervous system diseases

Antibody-mediated central nervous system diseases are a relatively new area of clinical neuroscience with growing impact. Their recognition has challenged the dogma of the blood–brain barrier preventing antibody access into the central nervous system. The antibodies discovered so far are mainly against neurotransmitter receptors (e.g. N-methyl-d-aspartate and glycine receptors) and ion channel–associated proteins (leucine-rich glioma inactivated protein 1 and contactin-associated protein 2) and are expressed on the surface of neuronal synapses and elsewhere. The disorders are reversible with immunotherapies that reduce antibody levels. Although rare, the identification of these disorders in clinical practice has made central nervous system autoimmune diseases a consideration in the differential diagnoses of many clinical presentations. There is still much to learn about the aetiology of the diseases and the mechanisms by which the antibodies act, the neuronal and glial changes that follow antibody-attack, and the compensatory changes that may be required to ensure good recovery.

Immunopathology in drug resistant mesial temporal lobe epilepsy with different types of hippocampal sclerosis

ABSTRACTPurpose: There is evidence that autoimmunity has a specific role in temporal lobe seizures of limbic encephalitis patients. Our aim in this study was to investigate any histopathological clues of autoimmune process in refractory temporal lobe epilepsy (TLE) patients with different pathologically proven hippocampal sclerosis (HS) types.Methods: 22 patients who had undergone epilepsy surgery due to mesial TLE-HS were included. The sera of patients are tested for neuronal antibodies to N-methyl-D-aspartate receptors (NMDAR), leucine-rich, glioma inactivated 1 (LGI1), contactin-associated protein 2 (CASPR2), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), gamma-aminobutyric acid B receptor (GABABR) and glutamic acid decarboxylase (GAD). Pathological and immunohistochemical investigations including neuronal nuclei (NeuN), NMDAR, GAD, glial fibrillary acidic protein (GFAP), CD8+-CD3+ lymphocytes and immunoglobulin G (IgG) were done. Patients were grouped according to type of HS. Clinical features and immunohistochemical changes were defined in these groups.Results: Available sera of 15 patients did not have any neuronal antibodies. Thirteen of 22 patients had HS type 1, three had HS type 2 and two had HS type 3. According to immunohistochemical investigations CD3+ and CD8+ T cell infiltration was more prominent in the hippocampus of patients with classical HS (International League Against Epilepsy (ILAE) Type 1 HS) and there was a significant negative correlation between epilepsy duration and numbers of CD3+-CD8+ lymphocytes in temporal lobe parenchyma.Conclusion: The role of T cell-mediated immunopathology and immunopathological difference in a variety of drug resistant TLE-H2S patients was suggested. These findings can be helpful in understanding the epileptogenicity of HS.

Antibodies against peripheral nerve antigens in chronic inflammatory demyelinating polyradiculoneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous disease in which diverse autoantibodies have been described but systematic screening has never been performed. Detection of CIDP-specific antibodies may be clinically useful. We developed a screening protocol to uncover novel reactivities in CIDP. Sixty-five CIDP patients and 28 controls were included in our study. Three patients (4.6%) had antibodies against neurofascin 155, four (6.2%) against contactin-1 and one (1.5%) against the contactin-1/contactin-associated protein-1 complex. Eleven (18.6%) patients showed anti-ganglioside antibodies, and one (1.6%) antibodies against peripheral myelin protein 2. No antibodies against myelin protein zero, contactin-2/contactin-associated protein-2 complex, neuronal cell adhesion molecule, gliomedin or the voltage-gated sodium channel were detected. In IgG experiments, three patients (5.3%) showed a weak reactivity against motor neurons; 14 (24.6%) reacted against DRG neurons, four of them strongly (7.0%), and seven (12.3%) reacted against Schwann cells, three of them strongly (5.3%). In IgM experiments, six patients (10.7%) reacted against DRG neurons, while three (5.4%) reacted against Schwann cells. However, results were not statistically significant when compared to controls. Immunoprecipitation experiments identified CD9 and L1CAM as potential antigens, but reactivity could not be confirmed with cell-based assays. In summary, we describe a diverse autoantibody repertoire in CIDP patients, reinforcing the hypothesis of CIDP’s pathophysiological heterogeneity.

Autoimmune encephalitis and sleep disorders

Research shows that autoimmune encephalitis is associated with sleep disorders. Paraneoplastic neurological syndrome (PNS) with Ma2 antibodies can cause sleep disorders, particularly narcolepsy and rapid eye movement sleep behavior disorder (RBD). Limbic encephalitis (LE) and Morvan syndrome, associated with voltage - gated potassium channel (VGKC)-complex antibodies, which include leucine-rich glioma-inactivated 1 (LGI1) antibody and contactin-associated protein 2 (Caspr2), can result in profound insomnia and other sleep disorders. Central neurogenic hypoventilation are found in patients with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, whereas obstructive sleep apnea (OSA), stridor and parasomnia are prominent features of encephalopathy associated with IgLON5 antibodies. Sleep disorders are cardinal manifestations in patients with autoimmune encephalitis. Immunotherapy possiblely can improve clinical symptoms and prognosis in a positive way. DOI: 10.3969/j.issn.1672-6731.2017.10.004

Paraneoplastic neuropathies.

To review recent advances in paraneoplastic neuropathies with emphasis on their definition, different forms and therapeutic development. A strict definition of definite paraneoplastic neuropathies is necessary to avoid confusion. With carcinoma, seronegative sensory neuronopathies and neuronopathies and anti-Hu and anti-CV2/Contactin Response Mediator Protein 5 antibodies are the most frequent. With lymphomas, most neuropathies occur with monoclonal gammopathy including AL amyloidosis, Polyneuropathy-Organomegaly-Endocrinopathy-M component-Skin changes (POEMS) syndrome, type I cryoglobulinemia and antimyelin-associated glycoprotein (MAG) neuropathies and Waldenström's disease. Neuropathies improving with tumor treatment are occasional, occur with a variety of cancer and include motor neuron disease, chronic inflammatory demyelinating neuropathy and nerve vasculitis. If antibodies toward intracellular antigens are well characterized, it is not the case for antibodies toward cell membrane proteins. Contactin-associated protein-2 antibodies occur with neuromyotonia and thymoma with the Morvan's syndrome in addition to Netrin 1 receptor antibodies but may not be responsible for peripheral nerve hyperexcitability. The treatment of AL amyloidosis, POEMS syndrome, anti-MAG neuropathy and cryoglobulinemia is now relatively well established. It is not the case with onconeural antibodies for which the rarity of the disorders and a short therapeutic window are limiting factors for the development of clinical trials. A strict definition of paraneoplastic neuropathies helps their identification and is necessary to allow an early diagnosis of the underlying tumor.

Brain-relevant antibodies in first-episode psychosis: a matched case-control study.

There has been much recent excitement about the possibility that some cases of psychosis may be wholly due to brain-reactive antibodies, with antibodies to N-methyl-D-aspartate receptor (NMDAR) and the voltage-gated potassium channel (VGKC)-complex reported in a few patients with first-episode psychosis (FEP). Participants were recruited from psychiatric services in South London, UK, from 2009 to 2011 as part of the Genetics and Psychosis study. We conducted a case-control study to examine NMDAR and VGKC-complex antibody levels and rates of antibody positivity in 96 patients presenting with FEP and 98 controls matched for age and sex. Leucine-rich glioma inactiviated-1 (LGI1) and contactin-associated protein (CASPR) antibodies were also measured. Notably, patients with suspicion of organic disease were excluded. VGKC-complex antibodies were found in both cases (n = 3) and controls (n = 2). NMDAR antibody positivity was seen in one case and one control. Either LGI1-Abs or CASPR2-Abs were found in three cases and three controls. Neuronal antibody staining, consistent with the above results or indicating potential novel antigens, was overall positive in four patients but also in six controls. Overall, antibody positivity was at low levels only and not higher in cases than in controls. This case-control study of the prevalence of antibodies in FEP does not provide evidence to support the hypothesis that FEP is associated with an immune-mediated process in a subgroup of patients. Nevertheless, as other bio-clinical factors may influence the effect of such antibodies in a given individual, and patients with organic neurological disease may be misdiagnosed as FEP, the field requires more research to put these findings in context.

P.171 - CNTNAP1: Extending the phenotype of congenital hypomyelinating neuropathy in 6 further patients

CNTNAP1 (OMIM # 602346) encodes rat contactin-associated protein (CASPR) and was first implicated in human disease in 2014.1 CASPR2, forms part of a high molecular mass complex in the paranodal junction and interacts with contactin. Normal paranodal junctions do not form if CASPR is absent and this occurs in conjunction with disruption of the paranodal loops. Using a whole exome sequencing (WES) approach in 31 non-syndromic arthrogryposis multiplex congenital families, Laquerriere et al identified four unrelated familes with homozygous frameshift mutations in CNTNAP1. Death occurred within the first 40 days of life in all four cases. CNTNAP1 has since been described in association with a severe congenital hypomyelinating neuropathy (CHN) in a further 5 patients in the literature. We describe the clinical findings in 6 further patients extending the phenotype beyond that of neonatal lethality. We report neuropathological findings on muscle and nerve biopsy of 3 of the patients. Further molecular genetic analysis is ongoing and the results will be reported. Our findings demonstrate that CNTNAP1 causes a reproducible specific phenotype of polyhydramnios with associated premature birth, severe central hypotonia from birth with severe demyelinating peripheral neuropathy, cranial nerve involvement including orobulbar dysfunction, vocal cord palsy, severe respiratory distress from birth with associated requirement for tracheostomy and profound intellectual disability. Onion bulb fibres were noted on neuropathological specimens concurring with previous reports, although not specific to CNTNAP1. Brain MRI demonstrated a varying combination of central hypomyelination, delayed myelination and loss of white matter bulk. This specific clinical pattern has not been previously reported in association with any of the other genes associated with CHN and should guide clinical management and genetic counselling.

Developmental Disruption of GABAAR-Meditated Inhibition in Cntnap2 KO Mice.

GABA released from presynaptic sites induces short-lived phasic inhibition mediated by synaptic GABAA receptors (GABAARs) and longer-duration tonic inhibition mediated by extrasynaptic GABAA or GABAB receptors (GABABRs). A number of studies have found that contactin-associated protein 2 (Cntnap2) knockout (KO) mice, a well-established mouse model of autism, exhibit reduced interneuron numbers and aberrant phasic inhibition. However, little is known about whether tonic inhibition is disrupted in Cntnap2 KO mice and when the disruption of inhibition begins to occur during postnatal development. We examined tonic and phasic inhibition in layer 2/3 pyramidal cells of primary visual cortex of Cntnap2 KO at two different developmental stages, three to four and six to eight weeks of age. We found that both phasic inhibition and GABAAR but not GABABR-mediated tonic inhibition was reduced in pyramidal cells from six- to eight-week-old Cntnap2 KO mice, while in three- to four-week-old mice, no significant effects of genotype on tonic or phasic inhibition was observed. We further found that activation of tonic currents mediated by δ-subunit-containing GABAARs reduced neural excitability, an effect that was attenuated by loss of Cntnap2. While the relative contribution of tonic versus phasic inhibition to autism-related symptoms remains unclear, our data suggest that reduced tonic inhibition may play an important role, and δ-subunit-containing GABAARs may be a useful target for therapeutic intervention in autism.

Molecular Disorganization of Axons Adjacent to Human Cortical Microinfarcts.

Cortical microinfarcts (CMIs) are microscopically identified wedge-shaped ischemic lesions that occur at or near the cortical surface and result from occlusion of penetrating arterioles. These microscopic lesions can be observed with high-resolution magnetic resonance imaging in aging brains and in patients with cerebrovascular disease. Recent studies have suggested that strategically located microinfarcts strongly correlate with cognitive deficits, which can contribute to Alzheimer’s disease as well as other forms of dementia. We have recently shown that the molecular organization of axons into functional microdomains is altered in areas adjacent to white matter lacunar and microinfarcts, creating a peri-infarct penumbral injury in surviving axons. Whether similar changes in nodal, adjacent paranodal, and proximal axon initial segment molecular organization occur in the cortex adjacent to human CMIs is not known. Paraffin-embedded sections of autopsy brain tissue from five patients with CMIs were immunofluorescently labeled for nodal and paranodal markers including beta-IV spectrin, ankyrin-G, and contactin-associated protein. High magnification images from the peri-infarct cortical tissue were generated using confocal microscopy. In surviving cortical tissue adjacent to microinfarcts, we observed a dramatic loss of axon initial segments, suggesting that neuronal firing capacity in adjacent cortical tissue is likely compromised. The number of identifiable nodal/paranodal complexes in surviving cortical tissue is reduced adjacent to microinfarcts, while the average paranodal length is increased indicating a breakdown of axoglial contact. This axonal microdomain disorganization occurs in the relative absence of changes in the structural integrity of myelinated axons as measured by myelin basic protein and neurofilament staining. These findings indicate that the molecular organization of surviving axons adjacent to human CMIs is abnormal, reflecting lost axoglial contact and the functional elements necessary for neural transmission. This study provides support for the concept of a microinfarct penumbral injury that may account for the cumulative cognitive effect of these tiny strokes.

Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelination polyneuropathy is a heterogeneous and treatable immune-mediated disorder that lacks biomarkers to support diagnosis. Recent evidence indicates that paranodal proteins (contactin 1, contactin-associated protein 1, and neurofascin-155) are the targets of autoantibodies in subsets of patients showing distinct clinical presentations. Here, we identified neurofascin-186 and neurofascin-140 as the main targets of autoantibodies in five patients presenting IgG reactivity against the nodes of Ranvier. Four patients displayed predominantly IgG4 antibodies, and one patient presented IgG3 antibodies that activated the complement pathway in vitro. These patients present distinct clinical features compared to those with anti-neurofascin-155 IgG4. Most patients had a severe phenotype associated with conduction block or decreased distal motor amplitude. Four patients had a subacute-onset and sensory ataxia. Two patients presented with nephrotic syndromes and one patient with an IgG4-related retroperitoneal fibrosis. Intravenous immunoglobulin and corticosteroids were effective in three patients, and one patient remitted following rituximab treatment. Clinical remission was associated with autoantibody depletion and with recovery of conduction block and distal motor amplitude suggesting a nodo-paranodopathy. Our data demonstrate that the pathogenic mechanisms responsible for chronic inflammatory demyelination polyneuropathy are broad and may include dysfunctions at the nodes of Ranvier in a subgroup of patients.

Axonal domain disorganization in Caspr1 and Caspr2 mutant myelinated axons affects neuromuscular junction integrity, leading to muscle atrophy.

Bidirectional interactions between neurons and myelinating glial cells result in formation of axonal domains along myelinated fibers. Loss of axonal domains leads to detrimental consequences on nerve structure and function, resulting in reduced conductive properties and the diminished ability to reliably transmit signals to the targets they innervate. Thus, impairment of peripheral myelinated axons that project to the surface of muscle fibers and form neuromuscular junction (NMJ) synapses leads to muscle dysfunction. The goal of our studies was to determine how altered electrophysiological properties due to axonal domain disorganization lead to muscle pathology, which is relevant to a variety of peripheral neuropathies, demyelinating diseases, and neurodegenerative disorders. Using conventional Contactin-Associated Protein 1 (Caspr1) and Caspr2 single or double mutants with disrupted paranodal, juxtaparanodal, or both regions, respectively, in peripheral myelinated axons, we correlated defects in NMJ integrity and muscle pathology. Our data show that loss of axonal domains in Caspr1 and Caspr2 single and double mutants primarily alters distal myelinated fibers together with presynaptic terminals, eventually leading to NMJ denervation and reduction in postsynaptic endplate areas. Moreover, reduction in conductive properties of peripheral myelinated fibers together with NMJ disintegration leads to muscle atrophy in Caspr1 mutants or muscle fiber degeneration accompanied by mitochondrial dysfunction in Caspr1/Caspr2 double mutants. Together, our data indicate that proper organization of axonal domains in myelinated fibers is critical for optimal propagation of electrical signals, NMJ integrity, and muscle health, and provide insights into a wide range of pathologies that result in reduced nerve conduction leading to muscle atrophy. © 2017 Wiley Periodicals, Inc.