Number Of Small Myelinated Fibers Research Articles

Deletion of GABA‐B Receptor in Schwann Cells Regulates Remak Bundles and Small Nociceptive C‐fibers

The mechanisms regulating the differentiation into non-myelinating Schwann cells is not completely understood. Recent evidence indicates that GABA-B receptors may regulate myelination and nociception in the peripheral nervous system. GABA-B receptor total knock-out mice exhibit morphological and molecular changes in peripheral myelin. The number of small myelinated fibers is higher and associated with altered pain sensitivity. Herein, we analyzed whether these changes may be produced by a specific deletion of GABA-B receptors in Schwann cells. The conditional mice (P0-GABA-B1(fl/fl)) show a morphological phenotype characterized by a peculiar increase in the number of small unmyelinated fibers and Remak bundles, including nociceptive C-fibers. The P0-GABA-B1(fl/fl) mice are hyperalgesic and allodynic. In these mice, the morphological and behavioral changes are associated with a downregulation of neuregulin 1 expression in nerves. Our findings suggest that the altered pain sensitivity derives from a Schwann cell-specific loss of GABA-B receptor functions, pointing to a role for GABA-B receptors in the regulation of Schwann cell maturation towards the non-myelinating phenotype.

Myelination in the human hippocampal formation from midgestation to adulthood

Myelination, one of the last steps of neuronal development, was examined in the human fetal and postnatal hippocampal formation using immunohistochemistry to detect a protein component of the myelin sheath, the myelin basic protein synthesized by oligodendroglial cells. Myelin basic protein-immunoreactive oligodendroglial cells were first seen at the 20th gestational week in the fimbria fornicis and in the alveus. Between the 21st and 35th weeks, myelinated axons also appeared in the fimbria fornicis. At the age of 39 gestational weeks, short and thin myelinated fibers were present in the fimbria, in the alveus, and less so in the stratum oriens of the hippocampus, while the first oligodendroglial cells appeared in the stratum lacunosum-moleculare and in the hilus. By the 2nd postnatal week myelinated fibers appeared in the stratum lacunosum-moleculare of Ammon's horn. At the 3rd month, myelination was strong in the alveus, moderate in the strata oriens, lacunosum-moleculare and radiatum of Ammon's horn, while only a small number of myelinated fibers were detected in the hilus. By the 5th month, the first oligodendroglial cells were detected in the molecular layer of the dentate gyrus. Myelination continued in the following years, particularly in the dentate gyrus, where even at the age of 11 years the density of myelinated fibers did not reach the adult level. It appears that the first myelinated axons belong to the long-projecting large hippocampal pyramidal cells and/or to their subcortical and cortical afferents. The sequence of myelination follows the known developmental pattern of hippocampal afferent and efferent pathways, and the prolonged myelination might be a factor in the prolonged functional maturation of hippocampal circuitry.

Metabotropic GABA-B receptors in the PNS: role in nociception and myelination

Event Abstract Back to Event Metabotropic GABA-B receptors in the PNS: role in nociception and myelination Valerio Magnaghi1*, M. Ballabio1, B. Bettler2, A. Faroni1 and P. Procacci3 1 University of Milan, Department of Endocrinology, Italy 2 University of Basel, Department of Biomedicine, Switzerland 3 University of Milan, Department of Human Morphology, Italy Metabotropic GABA-B receptors are present in the CNS where they play important roles in the modulation of nociceptive transmission and pain. Many preclinical studies reported that the GABA-B specific agonist baclofen is antinociceptive in different models of acute and chronic pain. The study of GABA-B1 knockout mice further supports the contribution of GABA-B receptors to central nociceptive processing. These mice are hyperalgesic, showing a reduced latency to thermal and mechanical stimuli. A tonic GABA-B receptor activation therefore appears to contribute to the establishment of the nociceptive threshold. Interestingly, GABA-B receptors are expressed in the peripheral nervous system (PNS), mainly in the Schwann cells where they control cell proliferation and myelination. Emerging evidence obtained in GABA-B1 knockout mice indicates that these mice exhibit gait alterations and reduced allodynic sensitivity too. Furthermore, GABA-B1-deficient mice show morphological and molecular changes in peripheral nerves, including an increase in the number of small myelinated fibers, as well as in small neurons of the lumbar dorsal root ganglia. These fibers are supposed to be A_ nociceptive fibers. Consequently, it has been suggested that GABA-B receptors are implicated in the PNS myelination process. The possibility that PNS alterations contribute to the sensory phenotypes observed in GABAB1- deficient mice has been also hypothesized. The study in conditional mice that specifically lack the GABA-B1 receptor in the Schwann cells or in motoneurons will aim to clarify the role of GABA-B receptors in peripheral pain sensitivity. Conference: 3rd Mediterranean Conference of Neuroscience , Alexandria, Egypt, 13 Dec - 16 Dec, 2009. Presentation Type: Oral Presentation Topic: Symposium 04 – Dis-inhibition processes in pain sensitization Citation: Magnaghi V, Ballabio M, Bettler B, Faroni A and Procacci P (2009). Metabotropic GABA-B receptors in the PNS: role in nociception and myelination. Front. Neurosci. Conference Abstract: 3rd Mediterranean Conference of Neuroscience . doi: 10.3389/conf.neuro.01.2009.16.019 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 19 Nov 2009; Published Online: 19 Nov 2009. * Correspondence: Valerio Magnaghi, University of Milan, Department of Endocrinology, Milan, Italy, valerio.magnaghi@unimi.it Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Valerio Magnaghi M. Ballabio B. Bettler A. Faroni P. Procacci Google Valerio Magnaghi M. Ballabio B. Bettler A. Faroni P. Procacci Google Scholar Valerio Magnaghi M. Ballabio B. Bettler A. Faroni P. Procacci PubMed Valerio Magnaghi M. Ballabio B. Bettler A. Faroni P. Procacci Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Neurophysiological, behavioral and morphological abnormalities in the Fabry knockout mice

Fabry disease (OMIM 301500) is a rare X-linked recessive disorder caused by mutations in the α-galactosidase gene (GLA). Loss of α-galactosidase (α-Gal) activity leads to the abnormal accumulation of glycosphingolipids in lysosomes predominantly of vascular endothelial cells. Clinically the disorder presents with angiokeratomas, clouding of the cornea, and renal, cardiac, and cerebrovascular complications. In addition, there is an increased incidence of neuropathic pain in Fabry patients. In this study, we investigated the implications of loss of α-galactosidase A activity on sensorimotor function and peripheral nervous system. Similar to the described in Fabry disease patients, the sensorimotor assessment of Fabry mice revealed diminished locomotor activity and warm hypoalgesia as assessed in the hot-plate. Moreover Fabry mice displayed alterations both in balance and co-ordination. By histological analysis, the cyto-architecture of Fabry mice sciatic nerves showed an increase in mean cross-sectional area accompanied by a decrease in the density of non-myelinated fibers as well as a trend for a decreased number of small myelinated fibers, a well established feature of Fabry disease. A relative preservation of large myelinated fibers and nerve conduction velocity measurements was observed. Our findings demonstrate for the first time that Fabry knockout mice have Gb3 accumulation in the peripheral nervous system, alterations in sensorimotor function, hypoalgesia and no impairment of motor nerve conduction.

Diffusion tensor quantification of the macrostructure and microstructure of human midsagittal corpus callosum across the lifespan

The midsagittal cross-sectional area of the human corpus callosum (CC) has been used by many researchers as a marker of development, natural aging, and neurodegenerative and acquired pathologies. The availability of non-invasive MRI methods for quantifying the macrostructural and microstructural organization of the CC would help to clarify the CC contribution to behavior and cognition in both health and disease. In this report, we extended and validated the ability of a recently described semi-automated diffusion tensor imaging tissue segmentation method to utilize the high orientation contrast of the CC on diffusion tensor imaging. Using a cohort of healthy right-handed children and adults aged 7-59 years, we show gender-independent non-linear (quadratic) and strongly correlated growth trends in the CC area and the corresponding diffusion tensor fractional anisotropy (r = 0.67; P < 1 x 10(-10)). Our results provide preliminary evidence that diffusion tensor anisotropy in the living CC may be related to the number of small myelinated fibers.

Altered peripheral myelination in mice lacking GABA B receptors

Emerging evidence implicates γ-aminobutyric acid type B (GABA B) receptors in peripheral nervous system (PNS) functions. In order to elucidate which biochemical, morphological and functional parameters of peripheral nerve fibers depend on GABA B receptors we studied GABA B1-deficient mice, which are devoid of functional GABA B receptors. Here, we show that GABA B1-deficient mice exhibit morphological and molecular changes in peripheral myelin, including an increase in the number of irregular fibers and increases in the expression levels of the myelin proteins PMP22 and P0. Moreover, the number of small myelinated fibers and small neurons of the lumbar dorsal root ganglia is higher in GABA B1-deficient mice than in wild-type littermates. We further show that GABA B1-deficient mice exhibit gait alterations and reduced allodynia. In summary, our findings implicate GABA B receptors in the PNS myelination process and raise the possibility that PNS alterations contribute to the sensory phenotypes of GABA B1-deficient mice.

September 13 Highlights

Sahenk et al. examined efficacy of NT-3 treatment in animal models and in a randomized controlled pilot trial in patients with CMT1A. NT-3 augmented axonal regeneration in the animal models, improved sensory scores of patients, and increased the number of small myelinated fibers in sural nerves. ![][1] figure. NT-3 treated (A), regenerating axons in (A), untreated (B), and BDNF treated nude mice (C) at 8 weeks. see page 681 The editorial by Pleasure and Chance considers the mechanism by which NT-3 enhances regeneration of myelinated axons in CMT1A, a disorder affecting primarily Schwann cells. NT-3 improves axonal degenerative disorders caused by neurotoxins such as pyridoxine and cisplatin. It may exert its therapeutic effects primarily on neuronal perikarya or axons. If this is correct, NT-3 therapy may enhance axonal maintenance and regeneration in CMT1A by substituting for the lack of normal Schwann cell tropic support that results from the excess Schwann cell synthesis of PMP22 in these patients. Alternatively, since Sahenk et al. observed that NT-3 treatment increased the numbers of Schwann cells in both nude mouse CMT1A xenografts and in Trembler-J sciatic nerve segments distal to a crush, the therapeutic effect of NT-3 in CMT1A … [1]: /embed/graphic-1.gif

Expression of peripheral myelin protein zero in sural nerve of patients with Charcot-Marie-Tooth disease 1B

A Charcot-Marie-Tooth disease 1B (CMT1B) family with a mutation of the Po gene is presented. A to G substitution of nucleotide 389 in exon 3 resulted in Lys 131 Arg substitution. Immunostaining for Po in biopsied sural nerve from one family member with CMT1B was expressed in a small number of myelinated fibers. Immunoblot analysis for Po revealed that it was of normal molecular weight (29 kDa) although significantly reduced in amount. This heterozygous mutation could lead to a reduction in the total amount of normal protein in peripheral nerves through a mechanism of loss of function.

Chronic compression model of the cauda equina: Histological and electrophysiological study

Histological and electrophysiological changes of the cauda equina caused by chronic compression with silicone film were assessed in the lumbar spine of adult cats. Twenty cats underwent laminectomy of the sixth lumbar vertebra. The animals were divided into four groups (n = 5 each). In three groups, the dura was covered with silicone film. The fourth group (sham-operated) served as controls. Histological and electrophysiological studies, using spinal cord evoked potentials (SpEPs) with high frequency stimulation (HFS) were performed after periods of 4, 12, and 24weeks. Controls were examined at 12weeks. Dilatation of the endoneurial microvessels was noted in two of five cats in the 4-week group and in all animals in the 12- and 24-week groups. The nerve fibers of the control animals and the animals in the 4-week group were normal, in the 12-week group, a decrease in the number of large myelinated fibers and an increase in the number of small myelinated fibers was seen in the dorsal and ventral nerve roots. Electrophysiologically, there was no significant difference in SpEPs before and after the silicone film coverage. Recovery of the peak latency was significantly delayed after HFS in the 24-week group. This model is considered to be useful in studying the pathophysiology of chronically compressed cauda equina.

Smaller number of large myelinated fibers and focal myelin thickening in mutant quails deficient in neurofilaments.

The peripheral nervous system of a mutant of a Japanese quail deficient in neurofilaments (mutant) and of a normal Japanese quail (control) was morphometrically evaluated to characterize the morphological findings, especially those of the myelinated fibers of the mutant. In the proximal peroneal nerves, the frequency of the teased myelinated fibers showing the focal myelin thickening was higher in mutant than in control (P < 0.001) without obvious ongoing axonal degeneration and segmental demyelination. The total numbers of the myelinated fibers in the proximal and distal peroneal nerve, and in the tibial nerve branch to gastrocnemius muscle (pars medialis) were similar between control and mutant, although the number of the large myelinated fibers was less (P < 0.01) and the number of the small myelinated fibers was greater (P < 0.01) in mutant compared with control. The median diameters of neuronal cell bodies of the sacral dorsal root ganglia were similar in control and mutant. The percentages of light, dark and unclassified cells evaluated based on the histologic cytoplasmic features were also similar in control and mutant. Therefore, morphometric alterations were more pronounced in the peripheral myelinated nerve fibers compared with those in the cell bodies of the spinal dorsal root ganglia. We concluded that a smaller number of large myelinated fibers with a greater number of small myelinated fibers and the presence of focal myelin thickening are the main morphologic findings in this mutant, probably due to the arrest of radial growth or maturation of the axons of the myelinated fibers in the absence of ongoing myelinated fiber degeneration.

Effect on the rat hypoglossal nucleus of vinblastine and colchicine applied to the intact or transected hypoglossal nerve

The possibility that interruption of axonal transport in otherwise intact axons induces retrograde neuronal and nonneuronal reactions was examined. In addition, the proposal that blockade of axonal transport proximal to nerve injury might inhibit or delay the axon reaction was examined. Cuffs containing various doses of vinblastine were applied to the intact hypoglossal nerve. Colchicine was applied in a similar way to the intact hypoglossal nerve, injected directly into the intact nerve, or administered proximal to the site of hypoglossal nerve transection. The effect on retrograde axonal transport in the nerve was evaluated in the vinblastine experiments by the retrograde horseradish peroxidase (HRP) technique following injection of HRP or wheat germ agglutinin-conjugated HRP into the tongue. A dose of 0.01% caused an almost complete, but transient, blockade of the retrograde transport of the tracer, and induced a clearcut chromatolytic reaction in hypoglossal neurons. The chromatolytic changes were accompanied by a significant increase in the number of glial cells, many of which were identified as microglia. Similar results were obtained with colchicine alone or in combination with nerve transection. Signs of Wallerian degeneration after vinblastine treatment (0.01%) were observed only in a small number of myelinated fibers. The findings are compatible with the view that depletion of retrogradely transported factors from the peripheral innervation territory (including the distal nerve stump) to the perikaryon and/or a premature return of anterogradely transported substances at the site of drug exposure are factors inducing retrograde neuronal and nonneuronal changes.