Myelin Sheath

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Background: Paclitaxel, a widely-used antineoplastic drug, produces a painful peripheral neuropathy that in rodents is associated with peripheral-nerve mitochondrial alterations. The sigma-1 receptor (σ 1 R) is a ligand-regulated molecular chaperone involved in mitochondrial calcium homeostasis and pain hypersensitivity. This receptor plays a key role in paclitaxel-induced neuropathic pain, but it is not known whether it also modulates mitochondrial abnormalities. In this study, we used a mouse model of paclitaxel-induced neuropathic pain to test the involvement of the σ 1 R in the mitochondrial abnormalities associated with paclitaxel, by using genetic (σ 1 R knockout mice) and pharmacological (σ 1 R antagonist) approaches. Results: Paclitaxel administration to wild-type (WT) mice produced cold-and mechanical-allodynia, and an increase in the frequency of swollen and vacuolated mitochondria in myelinated A-fibers, but not in C-fibers, of the saphenous nerve. Behavioral and mitochondrial alterations were marked at 10 days after paclitaxel-administration and had resolved at day 28. In contrast, paclitaxel treatment did not induce allodynia or mitochondrial abnormalities in σ 1 R knockout mice. Moreover, the prophylactic treatment of WT mice with BD-1063 also prevented the neuropathic pain and mitochondrial abnormalities induced by paclitaxel. Conclusions: These results suggest that activation of the σ 1 R is necessary for development of the sensory nerve mitochondrial damage and neuropathic pain produced by paclitaxel. Therefore, σ 1 R antagonists might have therapeutic value for the prevention of paclitaxel-induced neuropathy.

Jimpy is a shortened life-span murine mutant showing recessive sex-linked inheritance. The genetic defect consists of a point mutation in the PLP gene and produces a severe CNS myelin deficiency that is associated with a variety of complex abnormalities affecting all glial populations. The myelin deficiency is primarily due to a failure to produce the normal amount of myelin during development. However, myelin destruction and oligodendrocyte death also account for the drastic myelin deficit observed in jimpy. The oligodendroglial cell line shows complex abnormalities in its differentiation pattern, including the degeneration of oligodendrocytes through an apoptotic mechanism. Oligodendrocytes seem to be the most likely candidate to be primarily altered in a disorder affecting myelination, but disturbances affecting astrocytes and microglia are also remarkable and may have a crucial significance in the development of the jimpy disorder. In fact, the jimpy phenotype may not be attributed to a defect in a single cell but rather to a deficiency in the normal relations between glial cells. Evidences from a variety of sources indicate that the jimpy mutant could be a model for disturbed glial development in the CNS. The accurate knowledge of the significance of PLP and its regulation during development must be of vital importance in order to understand glial abnormalities in jimpy. q 1998 Elsevier Science B.V.

Neural stem cells (NSCs) and neural progenitors (NPs) in the mammalian neocortex give rise to the main cell types of the nervous system. The biological behavior of these NSCs and NPs is regulated by extracellular niche derived autocrine-paracrine signaling factors on a developmental timeline. Our previous reports [1, 2] have shown that chondroitin sulfate proteoglycan (CSPG) and ApolipoproteinE (ApoE) are autocrineparacrine survival factors for NSCs. NogoA, a myelin related protein, is expressed in the cortical ventricular zones where NSCs reside. However, the functional role of Nogo signaling proteins in NSC behavior is not completely understood. In this study, we show that NogoA receptors, NogoR1 and PirB, are expressed in the ventricular zone where NSCs reside between E10.5-14.5 but not at E15.5. Nogo ligands stimulate NSC survival and proliferation in a dosage dependent manner in vitro. NogoR1 and PirB, are low and high affinity Nogo receptors respectively, and are responsible for the effects of Nogo ligands on NSC behavior. Inhibition of autocrine-paracrine Nogo signaling blocks NSC survival and proliferation. In NSCs, NogoR1 functions through Rho whereas PirB uses Shp1/2 signaling pathways to control NSC behavior. Taken together, this work suggests that Nogo signaling is an important pathway for survival of NSCs.

The first aim of this study was the quantification of nerve fibres found in terminal branches of facial nerve and the second aim was the ultrastructural analysis of these terminal branches in order to observe their ultrastructural differences, if present. In the examination of literature; we could not find any studies related to this subject. Materials and methods: Four fresh frozen head and neck specimens were used and the dissections were done bilaterally. Therefore; totally 8 samples were examined. The samples were prepared according to routine transmission electron microscopic tissue preparation technique. The semi-thin sections were examined under light microscope by camera lucida. In every sample, the quantitative analysis was performed in 5 different areas in an area of 0.01 mm 2 and statistical analysis was done. Secondly; the ultrastructural appearance of these terminal branches were examined under transmission electron microscope. Results: In the quantitative analysis of terminal branches of facial nerve in an area of 0.01 mm 2 ; the least number of nerve fibres were found in temporal branches and the highest number were detected in cervical branches. In transmission electron microscopic examination, no significant difference was found in between these branches. In the statistical analysis; statistically significant differences were obtained in between the temporal and buccal, marginal mandibular, cervical branches; zygomatic and marginal mandibular, cervical branches; buccal and marginal mandibular, cervical branches; marginal mandibular and cervical branches. Conclusions: These numerical data will have an importance during the nerve repair process of terminal branches of facial nerve in various injuries.

Lysosomal storage diseases (LSDs) are typically caused by a deficiency in a soluble acid hydrolase and are characterized by the accumulation of undegraded substrates in the lysosome. Determining the role of specific cell types in the pathogenesis of LSDs is a major challenge due to the secretion and subsequent uptake of lysosomal hydrolases by adjacent cells, often referred to as "cross-correction." Here we create and validate a conditional mouse model for cell-autonomous expression of galactocerebrosidase (GALC), the lysosomal enzyme deficient in Krabbe disease. We show that lysosomal membrane-tethered GALC (GALCLAMP1) retains enzyme activity, is able to cleave galactosylsphingosine, and is unable to cross-correct. Ubiquitous expression of GAL-CLAMP1 fully rescues the phenotype of the GALC-deficient mouse (Twitcher), and widespread deletion of GALCLAMP1 recapitulates the Twitcher phenotype. We demonstrate the utility of this model by deleting GALCLAMP1 specifically in myelinating Schwann cells in order to characterize the peripheral neuropathy seen in Krabbe disease. lysosomal storage disease | Krabbe disease | mouse model L ysosomal storage disorders (LSDs) are a large class of met-

CNS myelination by oligodendrocytes requires directed transport of myelin membrane components and a timely and spatially controlled membrane expansion. In this study, we show the functional involvement of the R-solubleN-ethylmaleimide-sensitive factor attachment protein receptor (R-SNARE) proteins VAMP3/cellubrevin and VAMP7/TI-VAMP in myelin membrane trafficking. VAMP3 and VAMP7 colocalize with the major myelin proteolipid protein (PLP) in recycling endosomes and late endosomes/lysosomes, respectively. Interference with VAMP3 or VAMP7 function using small interfering RNA-mediated silencing and exogenous expression of dominant-negative proteins diminished transport of PLP to the oligodendroglial cell surface. In addition, the association of PLP with myelin-like membranes produced by oligodendrocytes cocultured with cortical neurons was reduced. We furthermore identified Syntaxin-4 and Syntaxin-3 as prime acceptor Q-SNAREs of VAMP3 and VAMP7, respectively. Analysis of VAMP3-deficient...

Macrophage activation and persistent inflammation contribute to the pathological process of spinal cord injury (SCI). It was reported that M2 macrophages were induced at 3-7 days after SCI but M2 markers were reduced or eliminated after 1 week. By contrast, M1 macrophage response is rapidly induced and then maintained at injured spinal cord. However, factors that modulate macrophage phenotype and function are poorly understood. We developed a model to distinguished bone marrow derived macrophages (BMDMs) from residential microglia and explored how BMDMs change their phenotype and functions in response to the lesion-related factors in injured spinal cord. Infiltrating BMDMs expressing higher Mac-2 and lower CX3CR1 migrate to the epicenter of injury, while microglia expressing lower Mac-2 but higher CX3CR1 distribute to the edges of lesion. Myelin debris at the lesion site switches BMDMs from M2 phenotype towards M1-like phenotype. Myelin debris activate ATP-binding cassette transporter A1 (ABCA1) for cholesterol efflux in response to myelin debris loading in vitro. However, this homeostatic mechanism in injured site is overwhelmed, leading to the development of foamy macrophages and lipid plaque in the lesion site. The persistence of these cells indicates a proinflammatory environment, associated with enhanced neurotoxicity and impaired wound healing. These foamy macrophages have poor capacity to phagocytose apoptotic neutrophils resulting in uningested neutrophils releasing their toxic contents and further tissue damage. In conclusion, these data demonstrate for the first time that myelin debris generated in injured spinal cord

A culture system that can recapitulate myelination in vitro will not only help us better understand the mechanism of myelination and demyelination, but also find out possible therapeutic interventions for treating demyelinating diseases. Here, we introduce a simple and reproducible myelination culture system using mouse motor neurons (MNs) and Schwann cells (SCs). Dissociated motor neurons are plated on a feeder layer of SCs, which interact with and wrap around the axons of MNs as they differentiate in culture. In our MN-SC coculture system, MNs survived over 3 weeks and extended long axons. Both viability and axon growth of MNs in the coculture were markedly enhanced as compared to those of MN monoculture. Co-labeling of myelin basic proteins (MBPs) and neuronal microtubules revealed that SC formed myelin sheaths by wrapping around the axons of MNs. Furthermore, using the coculture system we found that treatment of an antioxidant substance coenzyme Q10 (Co-Q10) markedly facilitated myelination. Myelin provides an electrically insulating material that forms a multilayered sheath around an axon of a neuron. In the peripheral nervous system (PNS), myelin sheath is generated by Schwann cells (SCs), whereas in the central nervous system (CNS), myelin is produced by oligodendrocytes. The myelin wrapping of axons by SCs and oligodendrocytes not only facilitates the conduction of action potentials in the nervous system, but also protects axons and provides nutritional support to associated axons. As various defects in myelination, such as hypomyelination, delayed myelination, or demyelination, are known to cause serious disorders in the nervous system 1-4 , understanding how SCs and oligodendrocytes initially produce myelin during development and remyelinate axons in the diseased nervous system is of significant clinical interest. In many cases of nerve repair after physical injury, an incomplete myelination of regenerated nerve fibers causes malfunction of repaired nerve 5 . To understand the process of myelination and remyelination, several in vitro models have been developed. Methods to culture SCs and oligodendrocytes have been established and extensively applied to investigate the biology of myelinating glia , and these cultures greatly improved the understanding of how SCs and oligodendrocytes differentiate and mature. In addition to culture systems comprising pure SCs or oligodendrocytes, coculture systems composed of both neurons and myelinating glia should provide insights into the interaction between myelination glial cells and axons as well as the myelinating process. To this end, previous studies described coculture systems of oligodendrocytes and hippocampal neurons 8 , SCs and sensory neurons (from dorsal root ganglia) 6 , or oligodendrocytes and retinal ganglion cells 9 . Recently, Gingras et al. 10 reported a method for culturing primary motor neurons (MNs) on collagen-chitosan sponges seeded with fibroblasts or with fibroblasts and Schwann cells, which enabled long-term culture (lasting more than a month) of MNs. However, the protocol required 21 days of

A Critical Period for Glia The brain develops in fits and starts—while one system is completed, another system may still be under construction. Such transient states are known as critical periods, and during these specific aspects of brain development may become more sensitive to outside agents than they would be later. Makinodan et al. (p. 1357 ) observed the effect of environmental conditions on the brains of mice bioengineered to develop fluorescent oligodendrocytes. The mice were exposed to a variety of social conditions during rearing, ranging from isolation to a normal laboratory cage setting, or to settings enriched with extra buddies and a steady rotation of new play toys. The results show that social isolation leaves a developmental trace that persists into adulthood. Specifically, they found that oligodendrocytes, which produce the myelin that insulates neurons, were underdeveloped, suggesting that there may be a critical period that governs development of these glial olig...

Schwann cells and oligodendrocytes are the myelinating cells of the peripheral and central nervous system, respectively. Despite having different myelin components and different transcription factors driving their terminal differentiation there are shared molecular mechanisms between the two. Sox10 is one common transcription factor required for several steps in development of myelinating glia. However, other factors are divergent as Schwann cells need the transcription factor Egr2/Krox20 and oligodendrocytes require Myrf. Likewise, some signaling pathways, like the Erk1/2 kinases, are necessary in both cell types for proper myelination. Nonetheless, the molecular mechanisms that control this shared signaling pathway in myelinating cells remain only partially characterized. The hypothesis of this study is that signaling pathways that are similarly regulated in both Schwann cells and oligodendrocytes play central roles in coordinating the differentiation of myelinating glia. To address this hypothesis, we have used genome-wide binding data to identify a relatively small set of genes that are similarly regulated by Sox10 in myelinating glia. We chose one such gene encoding Dual specificity phosphatase 15 (Dusp15) for further analysis in Schwann cell signaling. RNA interference and gene deletion by genome editing in cultured RT4 and primary Schwann cells showed Dusp15 is necessary for full activation of Erk1/2 phosphorylation. In addition, we show that Dusp15 represses expression of several myelin genes, including myelin basic protein. The data shown here support a mechanism by which Egr2 activates myelin genes, but also induces a negative feedback loop through Dusp15 in order to limit overexpression of myelin genes.

To describe the MR manifestations and temporal course of wallerian degeneration that occurs above and below a spinal cord injury, and to compare the MR findings with postmortem histopathology. Twenty-four postmortem spinal cords from patients with cervical (n = 14), thoracic (n = 6), and lumbar (n = 4) cord injuries were studied with axial T1- and T2-weighted spin-echo MR imaging. Injury-to-death intervals varied from 8 days to 23 years. The images were examined for alteration of signal above and below the injury site. Histologic studies of these cords with axon, myelin, and connective tissue stains were performed at levels equivalent to the MR sections. Immunohistochemical analysis using antibodies to glial fibrillary acetic protein was also performed on 19 cords. Pathologic-imaging comparisons were made. MR images showed increased signal intensity in the dorsal columns above the injury level and in the lateral corticospinal tracts below the injury level in all cases in which cord ...

Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain longterm axonal integrity . However, the underlying support mechanisms are not understood 4 . Here we identify ametabolic component of axon-glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors 5 , postmyelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations inmutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Becausemyelinated axons can use lactate when energy-deprived 6 , our findings suggest a model in which axon-glia metabolic coupling serves a physiological function.

Demyelinating diseases of the nervous system cause axon loss but the underlying mechanisms are not well understood. Here we show by confocal and electron microscopy that in myelin-forming glia peroxisomes are associated with myelin membranes. When peroxisome biogenesis is experimentally perturbed in Pex5 conditional mouse mutants, myelination by Schwann cells appears initially normal. However, in nerves of older mice paranodal loops become physically unstable and develop swellings filled with vesicles and electron-dense material. This novel model of a demyelinating neuropathy demonstrates that peroxisomes serve an important function in the peripheral myelin compartment, required for long-term axonal integrity.

Mutations of several genes encoding peroxisomal proteins have been associated with human diseases. Some of these display specific white matter abnormalities in the brain, although the affected proteins are ubiquitously expressed. To better understand the etiology of peroxisomal myelin diseases, we aimed to label these organelles in vivo and in a cell type specific fashion. We had previously shown that in oligodendrocytes and Schwann cells numerous peroxisomes reside in the cytoplasmic channels of "non-compacted" myelin. These organelles are smaller and biochemically distinct from non-myelin peroxisomes. Targeting peroxisomal functions in various cell types of the brain has demonstrated that oligodendroglial peroxisomes are specifically important for long-term integrity of the CNS. To visualize myelin peroxisomes in intact cells and tissues by live imaging, we have generated a novel line of transgenic mice for the expression of fluorescently tagged peroxisomes specifically in myelinating glia. This was achieved by modifying the gene for a photoconvertible mEos2 with a peroxisomal targeting signal type 1 (PTS1) and generating a fusion gene with the myelin-specific Cnp1 promoter. In the brain of resulting transgenic mice, peroxisomes are selectively labeled in oligodendrocytes. In this novel genetic tool, photoconversion of single peroxisomes from green to red fluorescence can be used to monitor the fate of single organelles and to determine the dynamics of PTS1mediated protein import in the context of myelin diseases that affect peroxisomal functions.

odes are etched in Pyrex, and immersed in an argon-xenon gas mixture that is ionized by the electrons and positrons (K. Pitts, Univ. Louisville, KY). This technology is still maturing -especially the vital gas purification and recycling system needed to avoid gain degradation -

Axonal ensheathment and myelination, one form of axon-sheath cell interaction, was studied under normal earth magnetism, in the absence of terrestrial magnetic field, and under a 5 G (0.0005 T) magnetic field. Results indicate that the geomagnetic field is necessary for the fundamental biological activity of axonal ensheathment and myelination. The exact mechanism of action remains obscure.

Deciphering the mechanisms regulating the generation of new neurons and new oligodendrocytes, the myelinating cells of the central nervous system, is of paramount importance to address new strategies to replace endogenous damaged cells in the adult brain and foster repair in neurodegenerative diseases. Upon brain injury, the extracellular concentrations of nucleotides and cysteinyl-leukotrienes (cysLTs), two families of endogenous signaling molecules, are markedly increased at the site of damage, suggesting that they may act as ''danger signals'' to alert responses to tissue damage and start repair. Here we show that, in brain telencephalon, GPR17, a recently deorphanized receptor for both uracil nucleotides and cysLTs (e.g., UDPglucose and LTD 4 ), is normally present on neurons and on a subset of parenchymal quiescent oligodendrocyte precursor cells. We also show that induction of brain injury using an established focal ischemia model in the rodent induces profound spatiotemporal-dependent changes of GPR17. In the lesioned area, we observed an early and transient up-regulation of GPR17 in neurons expressing the cellular stress marker heat shock protein 70. Magnetic Resonance Imaging in living mice showed that the in vivo pharmacological or biotechnological knock down of GPR17 markedly prevents brain infarct evolution, suggesting GPR17 as a mediator of neuronal death at this early ischemic stage. At later times after ischemia, GPR17 immunolabeling appeared on microglia/macrophages infiltrating the lesioned area to indicate that GPR17 may also acts as a player in the remodeling of brain circuitries by microglia. At this later stage, parenchymal GPR17 + oligodendrocyte progenitors started proliferating in the peri-injured area, suggesting initiation of remyelination. To confirm a specific role for GPR17 in oligodendrocyte differentiation, the in vitro exposure of cortical pre-oligodendrocytes to the GPR17 endogenous ligands UDPglucose and LTD 4 promoted the expression of myelin basic protein, confirming progression toward mature oligodendrocytes. Thus, GPR17 may act as a ''sensor'' that is activated upon brain injury on several embryonically distinct cell types, and may play a key role in both inducing neuronal death inside the ischemic core and in orchestrating the local remodeling/repair response. Specifically, we suggest GPR17 as a novel target for therapeutic manipulation to foster repair of demyelinating wounds, the types of lesions that also occur in patients with multiple sclerosis.

Apoptosis of oligodendrocytes (ODCs), the myelin-producing glial cells in the CNS, plays a central role in demyelinating diseases such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. To investigate the mechanism behind ODC apoptosis in EAE, we made use of conditional knockout mice lacking the adaptor protein FADD specifically in ODCs (FADDODC-KO). FADD mediates apoptosis by coupling death receptors with downstream caspase activation. In line with this, ODCs from FADDODC-KO mice were completely resistant to death receptor-induced apoptosis in vitro. In the EAE model, FADDODC-KO mice followed an ameliorated clinical disease course in comparison with control littermates. Lymphocyte and macrophage infiltration into the spinal cord parenchyma was significantly reduced, as was the extent of demyelination and proinflammatory gene expression. Collectively, our data show that FADD is critical for ODC apoptosis and the developm...

Animal models with selective genetic immunodeficiencies are useful tools to identify pathogenic mechanisms of disease. Resistant (C57BL/6F 129/J) (H-2b) mice are rendered susceptible to Theiler's murine encephalomyelitis virus-induced demyelination by genetic disruption of the beta 2 microglobulin gene [beta 2 m(-l-)]. The absence of beta 2 m prevents the expression of major histocompatibility complex class I molecules and normal levels of functional CD8+ T cells. We tested whether genetic depletion of beta 2 m would permit CNS remyelination after chronic demyelination induced by the Daniel's strain of Theiler's virus. In contrast to the minimal spontaneous remyelination observed in SJL/J mice after infection with the Daniel's strain of Theiler's virus, chronically infected beta 2 m(-I-) mice showed extensive and progressive spontaneous CNS remyelination at 6, 12, and 18 months after infection. Spontaneous remyelination by both oligodendrocytes and Schwann cells ...

Studying how the healthy human brain develops is important to understand early pathological mechanisms and to assess the influence of fetal or perinatal events on later life. Brain development relies on complex and intermingled mechanisms especially during gestation and first post-natal months, with intense interactions between genetic, epigenetic and environmental factors. Although the baby's brain is organized early on, it is not a miniature adult brain: regional brain changes are asynchronous and protracted, i.e. sensorymotor regions develop early and quickly, whereas associative regions develop later and slowly over decades. Concurrently, the infant/child gradually achieves new performances, but how brain maturation relates to changes in behaviour is poorly understood, requiring noninvasive in vivo imaging studies such as MRI. Two main processes of early white matter development are reviewed: 1) establishment of connections between brain regions within functional networks, leading to adult-like organisation during the last trimester of gestation, 2) maturation (myelination) of these connections during infancy to provide efficient transfers of information. Current knowledge from post-mortem descriptions and in vivo MRI studies is summed up, focusing on T1-and T2-weighted imaging, diffusion tensor imaging, and quantitative mapping of T1/T2 relaxation times, myelin water fraction and magnetization transfer ratio.

ABSTRACTChange in the timeline of neurobiological growth is an important source of biological variation, and thus phenotypic evolution. However, no study has to date investigated sensory system development in any of the prosimian primates that are thought to most closely resemble our earliest primate ancestors. Acetylcholine (ACh) is a neurotransmitter critical to normal brain function by regulating synaptic plasticity associated with attention and learning. Myelination is an important structural component of the brain because it facilitates rapid neuronal communication. In this work we investigated the expression of acetylcholinesterase (AChE) and the density of myelinated axons throughout postnatal development in the inferior colliculus (IC), medial geniculate complex (MGC), and auditory cortex (auditory core, belt, and parabelt) in Garnett's greater galago (Otolemur garnetti). We found that the IC and MGC exhibit relatively high myelinated fiber length density (MFLD) values a...

Nerve myelination facilitates saltatory action potential conduction and exhibits spatiotemporal variation during development associated with the acquisition of behavioral and cognitive maturity. Although human cognitive development is unique, it is not known whether the ontogenetic progression of myelination in the human neocortex is evolutionarily exceptional. In this study, we quantified myelinated axon fiber length density and the expression of myelin-related proteins throughout postnatal life in the somatosensory (areas 3b/3a/1/2), motor (area 4), frontopolar (prefrontal area 10), and visual (areas 17/18) neocortex of chimpanzees ( N = 20) and humans ( N = 33). Our examination revealed that neocortical myelination is developmentally protracted in humans compared with chimpanzees. In chimpanzees, the density of myelinated axons increased steadily until adult-like levels were achieved at approximately the time of sexual maturity. In contrast, humans displayed slower myelination du...

Methylprednisolone (MP) is a synthetic glucocorticoid used for the treatment of spinal cord injury (SCI). Soluble Nogo‐66 receptor (NgR) ectodomain is a novel experimental therapy for SCI that promotes axonal regeneration by blocking the growth inhibitory effects of myelin constituents in the adult central nervous system. To evaluate the potential complementarity of these mechanistically distinct pharmacological reagents we compared their effects alone and in combination after thoracic (T7) dorsal hemisection in the rat. Treatment with an ecto‐domain of the rat NgR (27–310) fused to a rat IgG [NgR(310)ecto‐Fc] (50 µm intrathecal, 0.25 µL/h for 28 days) or MP alone (30 mg/kg i.v., 0, 4 and 8 h postinjury) improved the rate and extent of functional recovery measured using Basso, Beattie, Bresnahan (BBB) scoring and footprint analysis. The effect of MP treatment on BBB score was apparent the day after SCI whereas the effect of NgR(310)ecto‐Fc was not apparent until 2 weeks after SCI. N...

The transmembrane protein ␤-DG Department of Physiology and Biophysics anchors ␣-DG, and the cytoplasmic domain of ␤-DG Department of Neurology interacts with dystrophin, which in turn binds to F-actin 2 Department of Pathology (Jung et al., 1995). Thus, DG stabilizes the plasma mem-3 Department of Obstetrics and Gynecology brane by acting as an axis through which the ECM is 4 Physical Therapy and Rehabilitation Science tightly linked to cytoskeleton. Deficiency of any of sev-Graduate Program eral DGC components or laminin 2 leads to muscular University of Iowa Roy J. and Lucille A. Carver dystrophy (Cohn and Campbell, 2000; Cohn et al., 2002). College of Medicine Dystroglycan is widely expressed also by nonmuscle Iowa City, Iowa 52242 tissues including peripheral nerve (Matsumura et al., 5 Department of Biological Science 1993). Although DG plays a role in the pathogenesis of School of Veterinary Medicine Mycobacterium leprae (M. leprae) neuropathy (Rambuk-Waisman Center kana et al., 1998), its normal functions in peripheral nerve University of Wisconsin are unknown. Dystroglycan is expressed by Schwann Madison, Wisconsin 53705 cells where it localizes to the outer membrane apposing 6 Centre for Neuroscience Research the basal lamina (Yamada et al., 1994; Saito et al., 1999; Department of Preclinical Veterinary Sciences Masaki et al., 2000). There, DG interacts with laminin 2 University of Edinburgh and agrin (Yamada et al., 1996) and forms a DGC-like EH9 1QH Edinburgh complex with Dp116 (Byers et al., 1993; Saito et al., United Kingdom 1999), a Schwann cell-specific alternatively spliced form 7 Department of Neurology of dystrophin, as well as with utrophin and sarcoglycans Mayo Clinic (Imamura et al., 2000). In addition, the dystrophin related Rochester, Minnesota 55905 protein 2 (DRP2)-L-periaxin complex binds to DG (Sher-8 San Raffaele Scientific Institute man et al., 2001). Importantly, mutations of L-periaxin DIBIT cause dysmyelinating peripheral neuropathy in humans 20132 Milano and mice (Gillespie et al., 2000; Boerkoel et al., 2001; Italy Guilbot et al., 2001). Many studies in vitro have indicated that the basal lamina, especially laminin 2, is important for Schwann cells to ensheath and myelinate axons Summary (Bunge et al., 1993). Furthermore, congenital muscular dystrophy patients and dy/dy mice deficient in laminin Dystroglycan is a central component of the dys-2 develop not only muscular dystrophy, but also dysmytrophin-glycoprotein complex implicated in the pathoelinating peripheral neuropathy (Matsumura et al., 1997). genesis of several neuromuscular diseases. Although These observations prompted us to hypothesize that dystroglycan is expressed by Schwann cells, its norlaminin receptors on the Schwann cell surface play a mal peripheral nerve functions are unknown. Here we crucial role in myelination by binding with and conveying show that selective deletion of Schwann cell dystrosignals from laminin 2. Dystroglycan is an excellent canglycan results in slowed nerve conduction and nodal didate for a laminin 2 receptor involved in myelination, changes including reduced sodium channel density because it is coexpressed with laminin 2 during periphand disorganized microvilli. Additional features of mueral nerve myelination and regeneration after nerve tant mice include deficits in rotorod performance, abcrush injury (Masaki et al., 2000, 2002). Furthermore, M. errant pain responses, and abnormal myelin sheath leprae or M. leprae components that bind DGC, such folding. These data indicate that dystroglycan is cruas phenolic glycolipid-1, cause demyelination in vitro cial for both myelination and nodal architecture. Dysand in vivo (Rambukkana et al., 2002). troglycan may be required for the normal maintenance The constitutive DG knockout is embryonic lethal (Wilof voltage-gated sodium channels at nodes of Ranvier, liamson et al., 1997), so to elucidate the role of DG in possibly by mediating trans interactions between peripheral nerve, we generated mice in which DG is Schwann cell microvilli and the nodal axolemma. disrupted selectively in Schwann cells using the P0 protein promoter and Cre-loxP technology. We show that the loss of DG causes severe neurological dysfunction

Remyelination of the CNS involves the regeneration of mature oligodendrocytes by endogenous oligodendrocyte progenitor cells (OPCs). Previous studies have shown that bone morphogenic proteins (BMPs) inhibit the production of oligodendrocytes in the healthy CNS. However, there is currently no information on the influence of BMP signalingin vivowithin demyelinated lesions of the brain or on subsequent remyelination. Here, we determine a role for BMP signaling in modulating oligodendrogliogenesis and remyelination in the brain following cuprizone-induced demyelination. We identified that BMP signaling is active in oligodendroglia and astrocytes within the demyelinated corpus callosum. Intraventricular infusion of BMP4 into the brains of mice during demyelination increased the proliferation of OPCs and, to a lesser extent, microglia and astrocytes in the corpus callosum. In contrast, infusion of Noggin, an extracellular antagonist of BMP4, increased the density of mature oligodendrocyte...

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Myelinated axons are constricted at nodes of Ranvier. These constrictions are important physiologically because they increase the speed of saltatory nerve conduction, but they also represent potential bottlenecks for the movement of axonally transported cargoes. One type of cargo are neurofilaments, which are abundant space-filling cytoskeletal polymers that function to increase axon caliber. Neurofilaments move bidirectionally along axons, alternating between rapid movements and prolonged pauses. Strikingly, axon constriction at nodes is accompanied by a reduction in neurofilament number that can be as much as 10-fold in the largest axons. To investigate how neurofilaments navigate these constrictions, we developed a transgenic mouse strain that expresses a photoactivatable fluorescent neurofilament protein in neurons. We used the pulse-escape fluorescence photoactivation technique to analyze neurofilament transport in mature myelinated axons of tibial nerves from male and female m...

In most cases of hereditary neuropathy with liability to pressure palsy (HNPP) the diagnosis is now assessed by molecular detection of 17p11.2 deletion. However, the family history may be missing and the clinical presentation is not always informative. In such cases, a peripheral nerve biopsy showing the characteristic focal myelin sheath thickening (''tomaculae'') may be helpful. We present a retrospective study of peripheral nerve biopsies performed in 19 patients suffering from either a mononeuropathy or a generalized sensory-motor polyneuropathy, and for whom the finding of tomaculae led to a search for 17p11.2 deletion, which was confirmed secondarily. Tomaculae and other coexisting neuropathological lesions such as uncompacted myelin, ''onion bulb'' formations, and axonal degeneration are described and discussed in the view of previously reported data. It appears that demyelinating lesions with tomaculae are strongly suggestive of HNPP but are not specific as they may be observed in other conditions. Moreover, these features may be overlooked if axonal degeneration is marked.

Animal models with selective genetic immunodeficiencies are useful tools to identify pathogenic mechanisms of disease. Resistant (C57BL/6F 129/J) (H-2b) mice are rendered susceptible to Theiler's murine encephalomyelitis virus-induced demyelination by genetic disruption of the beta 2 microglobulin gene [beta 2 m(-l-)]. The absence of beta 2 m prevents the expression of major histocompatibility complex class I molecules and normal levels of functional CD8+ T cells. We tested whether genetic depletion of beta 2 m would permit CNS remyelination after chronic demyelination induced by the Daniel's strain of Theiler's virus. In contrast to the minimal spontaneous remyelination observed in SJL/J mice after infection with the Daniel's strain of Theiler's virus, chronically infected beta 2 m(-I-) mice showed extensive and progressive spontaneous CNS remyelination at 6, 12, and 18 months after infection. Spontaneous remyelination by both oligodendrocytes and Schwann cells ...

Tissue was prepared for high-resolution EM as described in Materials and Methods. Myelin g-ratio and myelin sheath integrity scores were determined using ImageJ software (National Institutes of Health, Bethesda, MD) by a blinded experimenter. For preliminary g-ratio analysis, axons selected for analysis (N = 100 axons/sample) were sampled from ≥ 3 fields in the midbody of the CC and had the appearance of completed myelination, i.e. complete myelin wrapping without delamination or damage. Selected axons were of varying diameters to assess whether myelination status was consistent across axons of different caliber. Cross-sectional axonal area was determined by hand-tracing the circumference of each axon without measuring myelin, and then again with the inclusion of the myelin sheath (myelinated axonal area). Axonal diameter (with and without myelin) was mathematically derived from each area measurement to prevent bias and g-ratio was calculated as follows: g = di/do, where di = inner axon diameter (also referred to as axon caliber) and do = diameter of axon plus myelin, i.e. outer myelinated diameter. Myelin integrity scoring was determined for a minimum of 100 axons in 3 fields using ImageJ. Each stage of myelination was scored using a numeric designation as follows: (1) unmyelinated axons, (2) partially myelinated axons, (3) completely myelinated axons with intact myelin, and (4) completely myelinated axons with damage. This scoring paradigm allowed the quantification of axons within each field (one field = ~696.8 μm 2 ). The average total axons per field is reported in Figure . Statistical analyses were conducted using JMP Pro 12.0 (SAS Institute Inc., Cary, NC). Myelin thickness, axon caliber, myelin g-ratio, myelin integrity scoring, and axon quantification were analyzed separately by sex or exposure via one-way ANOVA. Sexes were compared within exposure groups to determine any incidence of sex-specific effects. Linear regression and correlation analyses of both g-ratio and myelin thickness vs. axon caliber were performed with exposure group (CAPs or Air), axon caliber, and sex as between-group factors. Due to the limited sample size and exploratory nature of ultrastructural assessments, post hoc analyses for multiple comparisons were not performed. The tissue section/visual field was the experimental unit (i.e. replicate) for measures of myelin sheath thickness, g-ratio, axon caliber, myelin integrity scoring, and axon quantification. For correlative and linear regression analyses, each axon measurement was plotted individually. P-values ≤ 0.05 were considered statistically significant.

Nodes of Ranvier are regularly placed, nonmyelinated axon segments along myelinated nerves. Here we show that nodal membranes isolated from the central nervous system (CNS) of mammals restricted neurite outgrowth of cultured neurons. Proteomic analysis of these membranes revealed several inhibitors of neurite outgrowth, including the oligodendrocyte myelin glycoprotein (OMgp). In rat spinal cord, OMgp was not localized to compact myelin, as previously thought, but to oligodendroglia-like cells, whose processes converge to form a ring that completely encircles the nodes. In OMgp-null mice, CNS nodes were abnormally wide and collateral sprouting was observed. Nodal ensheathment in the CNS may stabilize the node and prevent axonal sprouting.

Intravenous immunoglobulin (IVIG) is an expensive medicine which is widely used for unlabeled indications. We conducted this drug utilization review (DUR) to evaluate the appropriateness of IVIG utilization in Tehran, Iran. This cross sectional study was conducted in a referral pediatric tertiary care hospital in Tehran. During a three month period in 2015, medical records of inpatients with IVIG order were evaluated. Appropriate indications for IVIG were determined based on the evidenced based guidelines and literature. Medical records of patients were reviewed and demographic data as well as the diagnosis, previous treatments, IVIG indication, dose, duration and the adverse drug reactions (ADR) were documented. Additionally, cost of therapy was calculated. During the study, 115 patients received IVIG. In 51 cases (44.4%), a total of 1338 gram IVIG was administered inappropriately. We found that in 32 cases (27.8%), intractable epilepsy was the inappropriate indication. The most fr...

Zika virus (ZIKV) is a reemerging human pathogen that causes congenital abnormalities, including microcephaly and eye disease. The cellular/molecular basis of ZIKV and host interactions inducing ocular and neuronal pathogenesis are unclear. Herein, we noted that the Hippo/Salvador-Warts-Hippo signaling pathway, which controls organ size through progenitor cell proliferation and differentiation, is dysregulated after ZIKV infection. In human fetal retinal pigment epithelial cells, there is an early induction of transcriptional coactivator, Yes-associated protein (YAP), which is later degraded with a corresponding activation of the TANK binding kinase 1/interferon regulatory factor 3 type I interferon pathway. YAP/transcriptional co-activator with a PDZ-binding domain (TAZ) silencing results in reduced ZIKV replication, indicating a direct role of Hippo pathway in regulating ZIKV infection. Using an in vivo Ifnar1 À/À knockout mouse model, ZIKV infection was found to reduce YAP/TAZ protein levels while increasing phosphorylated YAP Ser127 in the retina and brain. Hippo pathway is activated in major cellular components of the blood-brain barrier, including endothelial cells and astrocytes. In addition, this result suggests AMP-activated protein kinase signaling pathway's role in regulating YAP/TAZ in ZIKV-infected cells. These data demonstrate that ZIKV infection might initiate a cross talk among AMP-activated protein kinaseeHippoeTBK1 pathways, which could regulate antiviral and energy stress responses during oculoneuronal inflammation.

Oxidative damage and iron redistribution are associated with the pathogenesis and progression of multiple sclerosis (MS), but these aspects are not entirely replicated in rodent experimental autoimmune encephalomyelitis (EAE) models. Here, we report that oxidative burst and injury as well as redistribution of iron are hallmarks of the MS-like pathology in the EAE model in the common marmoset. Active lesions in the marmoset EAE brain display increased expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p22phox, p47phox, and gp91phox) and inducible nitric oxide synthase immunoreactivity within lesions with active inflammation and demyelination, coinciding with enhanced expression of mitochondrial heat-shock protein 70 and superoxide dismutase 1 and 2. The EAE lesion-associated liberation of iron (due to loss of ironcontaining myelin) was associated with altered expression of the iron metabolic markers FtH1, lactoferrin, hephaestin, and ceruloplasmin. The enhanced expression of oxidative damage markers in inflammatory lesions indicates that the enhanced antioxidant enzyme expression could not counteract reactive oxygen and nitrogen species-induced cellular damage, as is also observed in MS brains. This study demonstrates that oxidative injury and aberrant iron distribution are prominent pathological hallmarks of marmoset EAE thus making this model suitable for therapeutic intervention studies aimed at reducing oxidative stress and associated iron dysmetabolism.

Oxidative damage and iron redistribution are associated with the pathogenesis and progression of multiple sclerosis (MS), but these aspects are not entirely replicated in rodent experimental autoimmune encephalomyelitis (EAE) models. Here, we report that oxidative burst and injury as well as redistribution of iron are hallmarks of the MS-like pathology in the EAE model in the common marmoset. Active lesions in the marmoset EAE brain display increased expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p22phox, p47phox, and gp91phox) and inducible nitric oxide synthase immunoreactivity within lesions with active inflammation and demyelination, coinciding with enhanced expression of mitochondrial heat-shock protein 70 and superoxide dismutase 1 and 2. The EAE lesion-associated liberation of iron (due to loss of ironcontaining myelin) was associated with altered expression of the iron metabolic markers FtH1, lactoferrin, hephaestin, and ceruloplasmin. The enhanced expression of oxidative damage markers in inflammatory lesions indicates that the enhanced antioxidant enzyme expression could not counteract reactive oxygen and nitrogen species-induced cellular damage, as is also observed in MS brains. This study demonstrates that oxidative injury and aberrant iron distribution are prominent pathological hallmarks of marmoset EAE thus making this model suitable for therapeutic intervention studies aimed at reducing oxidative stress and associated iron dysmetabolism.

Degradation of the myelin sheath is a common pathology underlying demyelinating neurological diseases from Multiple Sclerosis to Leukodistrophies. Although large malformations of myelin ultrastructure in the advanced stages of Wallerian degradation is known, its subtle structural variations at early stages of demyelination remains poorly characterized. This is partly due to the lack of suitable and non-invasive experimental probes possessing sufficient resolution to detect the degradation. Here we report the feasibility of the application of an innovative non-invasive local structure experimental approach for imaging the changes of statistical structural fluctuations in the first stage of myelin degeneration. Scanning micro X-ray diffraction, using advances in synchrotron x-ray beam focusing, fast data collection, paired with spatial statistical analysis, has been used to unveil temporal changes in the myelin structure of dissected nerves following extraction of the Xenopus laevis sciatic nerve. The early myelin degeneration is a specific ordered compacted phase preceding the swollen myelin phase of Wallerian degradation. Our demonstration of the feasibility of the statistical analysis of SµXRD measurements using biological tissue paves the way for further structural investigations of degradation and death of neurons and other cells and tissues in diverse pathological states where nanoscale structural changes may be uncovered. N. Poccia et al. arXiv:1312.3669 [q-bio.BM] to be published in Scientific Reports (2014)

A serine-active enzyme, ''surfactant convertase,'' is required for the conversion of surfactant from the tubular myelin (TM) form to the small vesicular (SV) form. This transformation involves at least two steps, the conversion of TM to a surface-active film at the air-fluid interface and the reorientation of the film into the surface-inactive SV form; we asked if convertase was required for the first of these steps. Rat and mouse TMs were pretreated with diisopropyl fluorophosphate (DFP) to inactivate endogenous convertase activity or with vehicle and then were analyzed for their ability to lower surface tension in vitro as an index of the conversion of TM to a surface film. DFP pretreatment did not alter the ability of TM preparations to lower surface tension, as assessed by pulsating bubble, and it did not affect the behavior of TM in a surface balance. In an experiment designed to test the ability of TM to feed a surface film to exhaustion, TMs that had been pretreated with DFP or vehicle performed similarly. These experiments show that convertase activity is not required for the conversion of TM to a monolayer and suggest, instead, that convertase acts at a post surface film stage.

S U M M A R Y Pleiotrophin (PTN) is a member of the family of heparin-binding growth factors that displays mitogenic activities and promotes neurite outgrowth in vitro. In vivo, PTN is widely expressed along pathways of developing axons during the late embryonic and early postnatal period. Although the level of PTN gene expression is very low during adulthood, activation of the gene may occur during recovery from injury and seems to play an important role in tissue regeneration processes. In this study, we investigated whether PTN was involved in the regenerative process of injured peripheral nerves. To refer localization of the fluorescent markers to myelinated axons, we developed a specific computer tool for colocalization of fluorescence images with phase contrast images. Immunohistochemical analysis showed PTN in different types of nonneural cells in distal nerve segments, including Schwann cells, macrophages, and endothelial cells, but not in axons. Schwann cells exhibited PTN immunoreactivity as early as 2 days after injury, whereas PTN-positive macrophages were found 1 week later. Strong PTN immunoreactivity was noted in endothelial cells at all time points. These findings support the idea that PTN participates in the adaptive response to peripheral nerve injury. A better understanding of its contribution may suggest new strategies for enhancing peripheral nerve regeneration.

Blood-brain barrier (BBB) disruption alters the composition of the brain microenvironment by allowing blood proteins into the CNS. However, whether blood-derived molecules serve as extrinsic inhibitors of remyelination is unknown. Here we show that the coagulation factor fibrinogen activates the bone morphogenetic protein (BMP) signaling pathway in oligodendrocyte progenitor cells (OPCs) and suppresses remyelination. Fibrinogen induces phosphorylation of Smad 1/5/8 and inhibits OPC differentiation into myelinating oligodendrocytes (OLs) while promoting an astrocytic fate in vitro. Fibrinogen effects are rescued by BMP type I receptor inhibition using dorsomorphin homolog 1 (DMH1) or CRISPR/Cas9 activin A receptor type I (ACVR1) knockout in OPCs. Fibrinogen and the BMP target Id2 are increased in demyelinated multiple sclerosis (MS) lesions. Therapeutic depletion of fibrinogen decreases BMP signaling and enhances remyelination in vivo. Targeting fibrinogen may be an upstream therapeu...

Neurofilament medium (NF-M) is essential for the acquisition of normal axonal caliber in response to a myelin-dependent “outside-in” trigger for radial axonal growth. Removal of the tail domain and lysine-serine-proline (KSP) repeats of NF-M, but not neurofilament heavy, produced axons with impaired radial growth and reduced conduction velocities. These earlier findings supported myelin-dependent phosphorylation of NF-M KSP repeats as an essential component of axonal growth. As a direct test of whether phosphorylation of NF-M KSP repeats is the target for the myelin-derived signal, gene replacement has now been used to produce mice in which all serines of NF-M's KSP repeats have been replaced with phosphorylation-incompetent alanines. This substitution did not alter accumulation of the neurofilaments or their subunits. Axonal caliber and motor neuron conduction velocity of mice expressing KSP phospho-incompetent NF-M were also indistinguishable from wild-type mice. Thus, phospho...

Several neurological disorders, such as multiple sclerosis, the leukodystrophies, and traumatic injury, result in loss of myelin in the central nervous system (CNS). These disorders may benefit from cell-based therapies that prevent further demyelination or are able to restore lost myelin. One potential therapeutic strategy for these disorders is the manufacture of oligodendrocyte progenitor cells (OPCs) by the directed differentiation of pluripotent stem cells, including induced pluripotent stem cells (iPSCs). It has been proposed that OPCs could be transplanted into demyelinated or dysmyelinated regions of the CNS where they would migrate to the area of injury before terminally differentiating into myelinating oligodendrocytes. OPCs derived from mouse iPSCs are particularly useful for modeling this therapeutic approach and for studying the biology of oligodendrocyte progenitors because of the availability of mouse models of neurological disorders associated with myelin deficiency....

Jimpy is a shortened life-span murine mutant whose genetic disorder results in severe pathological alterations in the CNS, including Ž . hypomyelination, oligodendrocyte death and strong astroglial and microglial reaction. The knowledge of metallothionein MT regulation in the CNS and especially of MT presence in specific glial cell types under pathological conditions is scarce. In the present study, immunocytochemical detection of MT-I q II has been performed in spinal cord sections from 10-12-and 20-22-day-old jimpy and normal animals. The identification of MT-positive glial cells was achieved through double labeling combining MT immunocytochemistry and selective markers for oligodendrocytes, astrocytes and microglia. MT was found in glial cells and was present in the spinal cord of jimpy and normal mice at both ages, but there were remarkable differences in MT expression and in the nature of MT-positive glial cells depending on the type of mouse. The number of MT-positive cells was higher in jimpy than in normal spinal cords. This was apparent in all spinal cord areas, although it was more pronounced in white than in the gray matter and at 20-22 days than at 10-12 days. The mean Ž . Ž . number of MT-positive glia in the jimpy white matter was 1.9-fold 10-12 days and 2.4-fold 20-22 days higher than in the normal one. Astrocytes were the only parenchymal glial cells that were positively identified as MT-producing cells in normal animals. Interestingly, MT in the jimpy spinal cord was localized not only in astrocytes but also in microglial cells. The occurrence of MT induction in relation to reactive astrocytes and microglia, and its role in neuropathological conditions is discussed. q 1997 Elsevier Science B.V.

Theiler's virus infection of the CNS induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis (MS). Cannabinoids may act as immunosuppressive compounds that have shown therapeutic potential in chronic inflammatory disorders. Using the Theiler's murine encephalomyelitis virus model, we report here that treatment with the synthetic cannabinoids WIN 55,212–2, ACEA, and JWH-015 during established disease significantly improved the neurological deficits in a long-lasting way. At a histological level, cannabinoids reduced microglial activation, abrogated major histocompatibility complex class II antigen expression, and decreased the number of CD4+ infiltrating T cells in the spinal cord. Both recovery of motor function and diminution of inflammation paralleled extensive remyelination. Overall, the data presented may have potential therapeutic implications in demyelinating pathologies such as...

Voltage-gated sodium channels are largely localized to the nodes of Ranvier in myelinated axons, provid- ing a physiological basis for saltatory conduction. What hap- pens to these channels in demyelinated axons is not known with certainty. Experimentally demyelinated axons were examined by using a well-characterized polyclonal antibody directed against sodium channels. Immunocytochemical and radioim- munoassay data were consistent with the distribution of an increased number of sodium channels along segments of previously internodal axon. These findings affirm the plasticity of sodium channels in demyelinated axolemma and may be relevant to understanding how axons recover conduction after demyelination. Neurobiology: England et al. eases is demyelination of either the peripheral or central nervous system.

Voltage-gated sodium channels are largely localized to the nodes of Ranvier in myelinated axons, providing a physiological basis for saltatory conduction. What happens to these channels in demyelinated axons is not known with certainty. Experimentally demyelinated axons were examined by using a well-characterized, polyclonal antibody directed against sodium channels. Immunocytochemical and radioimmunoassay data were consistent with the distribution of an increased number of sodium channels along segments of previously internodal axon. These findings affirm the plasticity of sodium channels in demyelinated axolemma and may be relevant to understanding how axons recover conduction after demyelination.

Oligodendrocytes are essential regulators of axonal energy homeostasis and electrical conduction and emerging target cells for restoration of neurological function. Here we investigate the role of protease activated receptor 2 (PAR2), a unique protease activated G protein-coupled receptor, in myelin development and repair using the spinal cord as a model. Results demonstrate that genetic deletion of PAR2 accelerates myelin production, including higher proteolipid protein (PLP) levels in the spinal cord at birth and higher levels of myelin basic protein and thickened myelin sheaths in adulthood. Enhancements in spinal cord myelin with PAR2 loss-of-function were accompanied by increased numbers of Olig2- and CC1-positive oligodendrocytes, as well as in levels of cyclic adenosine monophosphate (cAMP), and extracellular signal related kinase 1/2 (ERK1/2) signaling. Parallel promyelinating effects were observed after blocking PAR2 expression in purified oligodendrocyte cultures, whereas ...

There have been previous reports of somatostatin-and acetylcholinesterase (AChE)-positive patches in the superficial layers of the presubiculum in monkeys. In this study, we show additional instances of patches in the presubiculum, as demonstrated by cytochrome oxidase (CO), by myelin and Nissl stains, and by the calcium-binding proteins calbindin (CB), calretinin (CR), and parvalbumin (PV). Markers are differentially expressed along the lateral and longitudinal axes. Comparisons of adjacent sections reacted for different markers suggest that the CB+ and CR+ patches, and CO+ and AChE+ patches generally correspond, but not the CB+ and CO+ patches. In cross section, patches are about 100-300 µm in width. Sections cut tangentially through the superficial layers indicate that the pattern of CO and AChE labeling is in fact patchlike in layer I, but that the apparent patches in layer II (CB and CR) form a reticular or lattice-like network. As patches are restricted to the presubiculum, these labeling patterns provide a convenient marker for the boundary between the presubiculum and the adjoining posteroventral retrosplenial cortex. More work is necessary to determine how this modularity may relate to the functional organization of the presubiculum.

Soluble immune complexes in cerebrospinal fluid of patients with multiple sclerosis and other neurological diseases GRACIELA GLIKMANN', S.-E. SVEHAG', E. HANS EN^, 0. HANSEN', s. HUSBY~, H. NIELSEN' AND c. FARRELL~ The occurrence of soluble immune complexes (IC) in the cerebrospinal fluid (CSF) of 14 multiple sclerosis (MS) patients, four acute polyradiculoneuritis patients, 30 patients with other neurological diseases (OND) and 30 patients with disc prolapse (DP) was examined by a solid phase Clq-protein A binding assay (Clq-PABA) and a complement consumption test. IC-positive reactions were observed only in the Clq-PABA. The binding indices determined by the Clq-PABA differed significantly (P < 0.01) when the MS or the OND patient groups were compared to the D P group. No significant (P < 0.1) difference was observed between the indices in the MS and OND groups. Binding indices in Clq-PABA showed n o correlation either t o IgG concentration, total protein concentration or cell counts in CSF of MS patients. Three of the four polyradiculoneuritis patients were strongly IC-positive while the fourth patient was negative. Filtration and PEG-precipitation data indicated that a major part of the IgG-containing IC in CSF detected by Clq-PABA was of macromolecular nature.