Glial and neuronal isoforms of Neurofascin have distinct roles in the assembly of nodes of Ranvier in the central nervous system

Rapid nerve impulse conduction in myelinated axons requires the concentration of voltage-gated sodium channels at nodes of Ranvier. Myelin-forming oligodendrocytes in the central nervous system (CNS) induce the clustering of sodium channels into nodal complexes flanked by paranodal axoglial junctions. However, the molecular mechanisms for nodal complex assembly in the CNS are unknown. Two isoforms of Neurofascin, neuronal Nfasc186 and glial Nfasc155, are components of the nodal and paranodal complexes, respectively. Neurofascin-null mice have disrupted nodal and paranodal complexes. We show that transgenic Nfasc186 can rescue the nodal complex when expressed in Nfasc(-/-) mice in the absence of the Nfasc155-Caspr-Contactin adhesion complex. Reconstitution of the axoglial adhesion complex by expressing transgenic Nfasc155 in oligodendrocytes also rescues the nodal complex independently of Nfasc186. Furthermore, the Nfasc155 adhesion complex has an additional function in promoting the migration of myelinating processes along CNS axons. We propose that glial and neuronal Neurofascins have distinct functions in the assembly of the CNS node of Ranvier.     

Lysophospholipids and their receptors in the central nervous system

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), two of the best-studied lysophospholipids, are known to influence diverse biological events, including organismal development as well as function and pathogenesis within multiple organ systems. These functional roles are due to a family of at least 11 G protein-coupled receptors (GPCRs), named LPA_1–6 and S1P_1–5, which are widely distributed throughout the body and that activate multiple effector pathways initiated by a range of heterotrimeric G proteins including G_i/o, G_12/13, G_q and G_s, with actual activation dependent on receptor subtypes. In the central nervous system (CNS), a major locus for these signaling pathways, LPA and S1P have been shown to influence myriad responses in neurons and glial cell types through their cognate receptors. These receptor-mediated activities can contribute to disease pathogenesis and have therapeutic relevance to human CNS disorders as demonstrated for multiple sclerosis (MS) and possibly others that include congenital hydrocephalus, ischemic stroke, neurotrauma, neuropsychiatric disorders, developmental disorders, seizures, hearing loss, and Sandhoff disease, based upon the experimental literature. In particular, FTY720 (fingolimod, Gilenya, Novartis Pharma, AG) that becomes an analog of S1P upon phosphorylation, was approved by the FDA in 2010 as a first oral treatment for MS, validating this class of receptors as medicinal targets. This review will provide an overview and update on the biological functions of LPA and S1P signaling in the CNS, with a focus on results from studies using genetic null mutants for LPA and S1P receptors. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.     

Ultrastructure of synapses in the central nervous system of lamellibranch molluscs.

Fine-structural characteristics of synaptic contacts were investigated in the central nervous system of different species of lamellibranch molluscs. Neuropile of the ganglia is characterized by regular occurrence of ultrastructurally well-defined polarized chemical synapses resembling those described in other invertebrate species and vertebrates. In addition to the generally observed membrane thickenings, enhanced density of synaptic membranes, cleft material and vesicle clustering on the presynaptic membrane, synapses are occasionally characterized by other and pinocytotic invaginations. Synaptic connections were distinguished on the basis of the vesicle content of the presynaptic terminal. Different forms of synaptic configurations (divergence, convergence, presynaptic modification) were observed in the ganglia.     

Chondroitin sulfates and their binding molecules in the central nervous system

Chondroitin sulfate (CS) is the most abundant glycosaminoglycan (GAG) in the central nervous system (CNS) matrix. Its sulfation and epimerization patterns give rise to different forms of CS, which enables it to interact specifically and with a significant affinity with various signalling molecules in the matrix including growth factors, receptors and guidance molecules. These interactions control numerous biological and pathological processes, during development and in adulthood. In this review, we describe the specific interactions of different families of proteins involved in various physiological and cognitive mechanisms with CSs in CNS matrix. A better understanding of these interactions could promote a development of inhibitors to treat neurodegenerative diseases.     

Microglia: activation and their significance in the central nervous system

Microglia are resident monocyte-lineaged cells in the brain. Their characteristic feature is that they react to injury and diseases of the brain and become morphologically and functionally activated. Although some trigger molecules which activate microglia are predicted to be released from injured or affected cells, such molecules have not yet been identified. The main role of activated microglia is believed to be in brain defense, as scavengers of dead cells, and as immune or immunoeffector cells. Recent biochemical and neurobiological studies have further indicated that they significantly affect the pathological state and/or regulate the regenerative state and remodeling of the brain by producing a variety of biologically active molecules including cytotoxic and neurotrophic molecules.     

Fibroblast growth factors and their receptors in the central nervous system

Fibroblast growth factors (FGFs) and their receptors constitute an elaborate signaling system that participates in many developmental and repair processes of virtually all mammalian tissues. Among the 23 FGF members, ten have been identified in the brain. Four FGF receptors (FGFRs), receptor tyrosine kinases, are known so far. Ligand binding of these receptors greatly depends on the presence of heparan sulfate proteoglycans, which act as low affinity FGFRs. Ligand binding specificity of FGFRs depends on the third extracellular Ig-like domain, which is subject to alternative splicing. Activation of FGFRs triggers several intracellular signaling cascades. These include phosphorylation of src and PLC leading finally to activation of PKC, as well as activation of Crk and Shc. SNT/FRS2 serves as an alternative link of FGFRs to the activation of PKC and, in addition, activates the Ras signaling cascade. In the CNS, FGFs are widely expressed; FGF-2 is predominantly synthesized by astrocytes, whereas other FGF family members, e.g., FGF-5, FGF-8, and FGF-9, are primarily synthesized by neurons. During CNS development FGFs play important roles in neurogenesis, axon growth, and differentiation. In addition, FGFs are major determinants of neuronal survival both during development and during adulthood. Adult neurogenesis depends greatly on FGF-2. Finally, FGF-1 and FGF-2 seem to be involved in the regulation of synaptic plasticity and processes attributed to learning and memory.     

Ultrastructure of the bimodal pacemaker neuron in the central nervous system of Helix pomatia L

Fine structure of the identified (RPal) giant neuron of Helix pomatia has been investigated after isolation. The following findings have been established: 1. The cytoplasm of the RPal neuron is electron-microscopically characterized by a strongly invaginated nuclear envelope, a highly-developed rER system, a large number of free ribosomes and by 110-250 nm-sized neurosecretory-like granules with finely-granulated inner content. 2. The fine-structural arrangement of the cytoplasm exhibited a seasonal variation, viz. in winter it was found to be layered, while in spring it showed a homogeneous structure. 3. On the cell surface free axon profiles containing vesicles were sometimes found, which might be afferent connections to the cell body.     

Are Ranvier's nodes of the central nervous system also artifacts by preparation?

Recent research on peripheral nerves of six species of vertebrates concluded that Ranvier's nodes may be artifacts by preparation. As a consequence, the question as to whether or not Ranvier's nodes of the central nervous system may also be artifacts was logically raised. The ultrastructural data concerning our field of research (the cerebellar cortex) support the notion that Ranvier's nodes are real features in the central nervous system; otherwise, the occurrence of vesicular outpockets establishing, along myelinated axons, well conspicuous en passant nodal synapses cannot be explained.     

Development of nodes of Ranvier

The architecture and function of the nodes of Ranvier depend on several specialized cell contacts between the axon and myelinating glial cells. These sites contain highly organized multimolecular complexes of ion channels and cell adhesion molecules, closely connected with the cytoskeleton. Recent findings are beginning to reveal how this organization is achieved during the development of myelinated nerves. The role of membrane proteins involved in axoglial interactions and of associated cytoplasmic molecules is being elucidated, while studies of mutant mice have underlined the importance of glial cells and the specific role of axonal proteins in the organization of axonal domains.     

Novel synaptic structures in the central nervous system of the locust Schlstocerca gregaria

Summary An electron-microscopical study of locust thoracic ganglia reveals that synapses in the neuropily are morphologically heterogeneous. In addition to the conventional dyadic type described frequently in the literature, there is a second type with a complex arrangement of presynaptic dense material and a non-dyadic postsynaptic configuration. Serial-section analysis of these synapses suggests that the presynaptic structures include irregular or curved bars, and small projections.Although the proportion of non-dyadic synapses in the neuropile as a whole is small, a substantial number have been found on the branches of an identified flight motor neurone, labelled intracellularly with metal ions in conjunction with silver intensification. Samples from the arborization of this neurone give some indications of the distribution of non-dyadic synapses on it.The results are discussed in the context of distribution of synapses on other identified locust neurones, and the functional morphology of synapses in other phyla.     

Age-related changes in lipid peroxidation in various structures of the central nervous system

Age-related changes in contents of lipid peroxidation (LPO) products and sensitivity to oxidative stress were studied in ten structures of the human brain and three parts of the spinal cord. LPO was found to increase with age in all parts of the central nervous system. This regularity was especially pronounced in the brainstem structures (the hypothalamus, mesencephalon, and myelencephalon) and in the cervical and sacrolumbar enlargements of the spinal cord.Translated from Fiziologiya Cheloveka, Vol. 31, No. 2, 2005, pp. 108–115.Original Russian Text Copyright © 2005 by Volchegorskii, Shemyakov, Telesheva, Malinovskaya, Turygin.     

Sprouting and formation of new synapses in motor structures of the central nervous system

The investigations of sprouting and reactive synaptogenesis in motor structures of the spinal cord, brain stem, thalamus, and cerebral cortex are reviewed. The reactions of the neurons and neuronal connections to injury and the ability of the nervous system to recover the impaired connections in the early postnatal period are compared with those in adult animals. The sprouting phenomenon appearing in the intact central nervous system is analyzed too. The mechanisms of synaptic reorganization of the nervous centers are discussed.Neirofiziologiya/Neurophysiology, Vol. 26, No. 4, pp. 299–314, June–July, 1994.