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New Approaches to Analyse Axon- Oligodendrocyte Communication In Neuroforum 2017; 23(4): A175–A181 Tim Czopka* and Franziska Auer New Approaches to Analyse Axon- Oligodendrocyte Communication in vivo https://doi.org/10.1515/nf-2017-A010 the temporal timing, with which signals are exchanged between neurons. Abstract: A major challenge for understanding our nerv- The regions in which axons exchange information ous system is to elucidate how its constituting cells coordi- between different brain areas are called the ‘white mat- nate each other to form and maintain a functional organ. ter’ (the grey matter being the areas where neuronal cell The interaction between neurons and oligodendrocytes bodies reside). White matter appears white due to the represents a unique cellular entity. Oligodendrocytes mye- presence of myelin, a fatty coating that surrounds most ax- linate axons by tightly ensheathing them. Myelination reg- ons. Myelin is an evolutionary acquisition of vertebrates, ulates speed of signal transduction, thus communication which electrically insulates axons and enables rapid between neurons, and supports long-term axonal health. and energy efficient signal transmission. It is likely that Despite their importance, we still have large gaps in our these properties have in fact enabled the evolution of our understanding of the mechanisms underlying myelinated complex nervous system with its high cell number. In the axon formation, remodelling and repair. Zebrafish repre- central nervous system (CNS), myelin is produced by spe- sent an increasingly popular model organism, particular- cialised glial cells, the Oligodendrocytes. Genetic defects ly due to their suitability for live cell imaging and genetic that perturb formation or maintenance of myelin (e.g. in manipulation. Here, we provide an overview about this Leukodystrophies) lead to severe motoric and cognitive research area, describe how zebrafish have helped under- symptoms. Similarly, degenerative myelin diseases lead standing mechanisms of myelination, and discuss how ze- to sensory-motor impairments and eventually paralysis, brafish may help addressing open questions related to the for example in Multiple Sclerosis (MS), an autoimmune control of axon-oligodendrocyte interactions. disease in which myelin is selectively destroyed. Further- Keywords: axon; in vivo imaging; myelin; oligodendro- more, there is increasing evidence that dynamic myelina- cyte, zebrafish tion is even involved in the regulation of brain plasticity and forms of learning, indicating that myelinating glia may play additional roles for nervous system function, be- yond their role as electrical insulator. We want to provide an overview of this area of re- search and emphasise how fundamental principles of the Introduction interaction between neurons and oligodendrocytes can be investigated using zebrafish as model organism. Our central nervous system comprises myriads of cells, which continuously communicate with each other to form a functional organ. Individual nerve cells (neurons) are connected via long process extensions (axons) to ex- Myelination of axons – more than change information. In doing so, neurons form a gigantic and highly complex network. Here, one important aspect static isolation for precise information processing is the speed, and thus Architecture of myelinated axons *Corresponding author: Tim Czopka, Technical University The term myelin as the ensheathment of axons dates back of Munich, Institute of Neuronal Cell Biology, Munich Clus- to 1854 by the German pathologist Rudolf Virchow. How- ter of Systems Neurology (SyNergy), Biedersteiner St. 29, ever, the identification of oligodendrocytes as the cellu- 80802 München, Germany, Mail: [email protected], Web: lar source of myelin did not happen until 1922 by Pio Del http://www.neuroscience.med.tum.de; https://www.czopka-lab.de Franziska Auer, Technical University of Munich, Institute of Neuronal Rio-Hortega. Since then, the structural, molecular and Cell Biology, Biedersteiner Str. 29, 80802 München, Germany, Mail: physiological properties of myelinated axons have been [email protected] defined quite well (Fig. 1). Each oligodendrocyte forms A176 Tim Czopka and Franziska Auer: New Approaches to Analyse Axon-Oligodendrocyte Communication Fig. 1: Cellular architecture of myelinated axons in the CNS A Cartoon showing a neuron with a myelinated axon (magenta), a myelinating oligodendrocyte (green) and an oligodendrozyte precursor cell (blue). B Schematic cross-sectional view of a myelinated axon. C Comparison of continuous (top) and saltatory (bottom) nerve conduction. In saltatory conduction, action potentials are only initiated at the nodes of Ranvier, which then ‘jumps’ from node to node. D Cartoon showing a longitudinal section through a myelinated axon around the node of Ranvier region. dozens of myelin segments (internodes), each of which thickness of the myelin, and the distance between the consists of tightly packed cell membranes, that are itera- nodes of Ranvier. In nature, however, myelination pat- tively ‘wrapped’ around the axon. The consecutive align- terns can greatly differ from the theoretically optimal pa- ment of individual internodes covers the axon along its rameters in order to precisely coordinate temporal control length, leaving only short unmyelinated gaps between of information flow. For example, it has been shown that each internode, the nodes of Ranvier, which are highly in the auditory system of the gerbil, action potential arriv- enriched in voltage gated Na+ channels (Fig. 1). The tight al times in the auditory brainstem are regulated by varia- stacking of myelin membrane electrically insulates the tion in internodal length. This enables precise control of axon. This insulation increases membrane resistance, so spatial hearing (Ford et al., 2015), and very nicely exem- that axon depolarisation spreads over a longer distance plifies that myelination patterns can be used to regulate with a lower potential drop than along an unmyelinated network function. axon. In consequence, the axon membrane is still suffi- In addition to highly specific myelination, completely ciently depolarised at distant nodes of Ranvier, so that atypical patterns of myelinated axons have been described resident Na+ channels can initiate a new action potential. recently. For example, axons of pyramidal neurons in the This way, the action potential seems to ‘jump’ from node adult cortex often show only discontinuous myelination to node. This type of saltatory conduction enables action with long, unmyelinated gaps (Tomassy et al., 2014). The potential propagation with up to 100m/s, whereby thick- functional repercussions of such patchy myelination are ness and length of the myelin amongst other factors affect currently totally unclear. However, in this context, it is in- conduction speed. teresting to note that adaptive myelination is involved in forms of learning. Acquisition of motor skills such as jug- gling involves white matter changes in humans. Similarly, Adapted and adaptive myelination to mice fail to learn complex motor tasks when the formation regulate nervous system function of new myelin was genetically prevented (McKenzie et al., 2014). Together, these findings are indicative that active It is possible to mathematically determine the optimal pa- communication between neurons and oligodendrocytes rameters for fastest action potential propagation, which may represent an additional regulatory element of higher are primarily affected by the thickness of the axon, the nervous system function. Tim Czopka and Franziska Auer: New Approaches to Analyse Axon-Oligodendrocyte Communication A177 Support of axon survival (Fig. 2). Furthermore, zebrafish are relatively easy to main- tain and they produce high numbers of offspring, which Enabling fast action potential propagation is not the only is why they were initially used mainly in mutagenesis role of myelinating glia. The tight cellular interaction be- screens to discover gene functions that underlie specific tween an axon and surrounding oligodendrocytes does phenotypes. not only provide electrical insulation, but also generally Young zebrafish represent a preeminent model or- isolates the axon from surrounding cells like astrocytes, ganism for neuroscience research. They have a relatively an important intermediate cell type for coupling neurons ‘simple’ nervous system, which does, however, control to vasculature. Neurons can have very long axons so that complex behaviours such as prey capture during their ear- the corresponding cell body can be over one meter away ly larval life. This necessitates the integration of sensory (in large animals). In order to meet the local energy de- information for the generation of an according behaviour. mands during action potential generation, myelinating Zebrafish are relatively easy to manipulate genetically. oli go dendro cytes supply axons with glycolysis metabo- Fertilised eggs can be injected with genetic constructs to lites (Saab et al., 2013). This ensures long-term axon sur- express any desired gene or to perturb its function. Due to vival. Indeed, it is plausible that lack of metabolic supply the optical transparency of young zebrafish, it is possible by oligdendrocytes contributes to axon degeneration in to investigate their CNS without the need of surgical inter- disease, for example when demyelinated axons do not get vention. Together, this allows to address neurobiological repaired in MS. questions from gene to behaviour in an intact organism. The current state of research shows
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