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Development of a Model for Microphysiological Simulations ISSN 1539–2791 Volume 3 • Number 2 • 2005 NeuroinformaticsNeuroinformatics IN THIS ISSUE Editors The Impact of the NIH Giorgio A. Ascoli Public Access Policy on Literature Informatics Erik De Schutter Statistical Criteria in fMRI Studies David N. Kennedy of Multisensory Integration Comparison of Vector Space Model Methodologies to Reconcile Cross-Species Neuroanatomical Concepts Development of a Model for Microphysiological Simulations Indexed and Abstracted in: Medline/Pubmed/Index Medicus Science Citation Index® HumanaJournals.com Search, Read, and Download NI_3_2_cvr 1 6/9/05, 11:36 AM Sosinsky.qxd 25/05/2005 04:08 pm Page 133 Neuroinformatics © Copyright 2005 by Humana Press Inc. All rights of any nature whatsoever are reserved. ISSN 1539-2791/05/133–162/$30.00 DOI: 10.1385/NI:03:02:133 Original Article Development of a Model for Microphysiological Simulations Small Nodes of Ranvier From Peripheral Nerves of Mice Reconstructed by Electron Tomography Gina E. Sosinsky1,*,Thomas J. Deerinck1, Rocco Greco1, Casey H. Buitenhuys1, Thomas M. Bartol 2 and Mark H. Ellisman1,* 1 National Center for Microscopy and Imaging Research, Department of Neurosciences and the Center for Research on Biological Systems, University of California, San Diego, CA2 Computational Neurobiology Laboratory, Salk Institute, La Jolla, CA Abstract ods, we have constructed accurate 3D models of the nodal complex from mouse spinal roots The node of Ranvier is a complex structure with resolution better than 7.5 nm. These recon- found along myelinated nerves of vertebrate structed volumes contain 75–80% of the thick- animals. Specific membrane, cytoskeletal, junc- ness of the nodal region. We also directly imaged tional, extracellular matrix proteins and the glial axonal junctions that serve to anchor organelles interact to maintain and regulate the terminal loops of the myelin lamellae to the associated ion movements between spaces in axolemma. We created a model of an intact node the nodal complex, potentially influencing of Ranvier by truncating the volume at its mid- response variation during repetitive activations point in Z, duplicating the remaining volume or metabolic stress. Understanding and building and then merging the new half volume with high resolution three dimensional (3D) structures mirror symmetry about the Z-axis. We added of the node of Ranvier, including localization of to this model the distribution and number of specific macromolecules, is crucial to a better Na+ channels on this reconstruction using tools understanding of the relationship between its associated with the MCell simulation program structure and function and the macromolecu- environment. The model created provides accu- lar basis for impaired conduction in disease. rate structural descriptions of the membrane Using serial section electron tomographic meth- compartments, external spaces, and formed *Authors to whom all correspondence and reprint requests should be addressed. E-Mail: [email protected]; [email protected] 133 Sosinsky.qxd 25/05/2005 04:08 pm Page 134 134 ____________________________________________________________________________Sosinsky et al. structures enabling more realistic simulations DOI: 10.1385/NI:03:02:133 of the role of the node in modulation of impulse propagation than have been conducted on Index Entries: Myelinated axons; peripheral myelinated nerve previously. nerve structure; saltatory conduction; ionic transmission; three-dimensional reconstruc- Abbreviations:PNS=peripheral nervous system, tion; electron microscopy; cell–cell junctions, CNS=central nervous system, HPF=high pressure axonal-glial interactions; high pressure freezing, EMT=electron microscopic tomography freezing. Introduction nodes of Ranvier represent an excellent exam- ple of structural specialization and organiza- The nodes of Ranvier allow amplification tion in that they contain highly regulated, and regeneration of action potentials and are recognizable membrane domains containing relatively recent evolutionary adaptations specific integral proteins, and distinct mor- found in most vertebrates. The first to observe phological structures connected to more than these structures was Louis-Antoine Ranvier one cell type. who in 1878 described the basic anatomical New methods for ultrastructural analysis are features as periodic constrictions of nerve available including methods for direct local- fibers. These specialized and complex struc- ization of macromolecules that have expanded tures reflect the functions these sites serve in our understanding of the structure of the nodal the saltatory propagation of large ionic cur- region. Concomitantly, our understanding of rents and the regeneration of resting mem- the structure/function relationship of the node brane potentials. Saltatory conduction allows of Ranvier has evolved from a simple site for more rapid propagation of action potentials concentration of ion channels, to one based on without large increases in axonal diameter and expanding knowledge of the node as an limits large ionic fluxes to very localized extremely complex and dynamic structure with domains of the nerve axons. Numerous stud- multiple ionic and metabolic compartments ies (Carley and Raymond, 1987; Endres et al., (see Fig. 1). Within the nodal complex there are 1986; Halter and Clark, 1993; Lev-Ram and also junctions of nearly every class (tight, gap, Ellisman, 1995; Lev-Ram and Grinvald, 1986; adherens, septate-like) including several Lev-Ram and Grinvald, 1987; Murray and formed between adjoining processes of the Steck, 1984; Wurtz and Ellisman, 1986) sup- same cells. In particular, the paranodal regions port the hypothesis that the axon/myelin/ of nodes of Ranvier contain gap junctions glial cell ensemble or “nodal complex” oper- (made up primarily of connexin32), the sep- ates in an integrated manner during conduc- tate-like axoglial junctions (containing the tion of the nerve impulse. Pathological proteins, caspr/paranodin and contactin, conditions in peripheral neuropathies occur (Boyle et al., 2001; Poliak et al., 2001; Tait et al., due to abnormalities in node of Ranvier con- 2000), and tight junctions (containing ZO1 and stituent proteins (Bergoffen et al., 1993; Griffin other tight junction proteins). Adherens junc- et al., 1996; Sima, 1993), axonal ischemic injury tions containing E-cadherin have cytoskeletal (Waxman et al., 1992) and trauma (Maxwell proteins such as F-actin, spectrin and beta- et al., 1991). Regeneration of damaged periph- catenin associated with them (Fannon et al., eral nerve axons also occurs at the nodes of 1995; Trapp et al., 1989). These adherens junc- Ranvier (Fawcett and Keynes, 1990). The tions connect the myelinating glia to the axon Neuroinformatics _______________________________________________________________ Volume 3, 2005 Sosinsky.qxd 25/05/2005 04:09 pm Page 135 Fig. 1. Continued. 135 Sosinsky.qxd 25/05/2005 04:09 pm Page 136 Fig. 1. Continued. 136 Sosinsky.qxd 25/05/2005 04:09 pm Page 137 3D Structure of the Node of Ranvier __________________________________________________________137 and myelin lateral loops to one another. Tight action at the node and paranode. Some of these junctions seal the periaxonal space of the para- membrane particles are Na+ channels that play nodal region from the intra-myelin space. In a a role in ionic conductance that occur at this system where fluctuations in state and dimen- site (Ellisman et al., 1982) and paranodal–axonal sions of compartments have been demon- junctional proteins such as Caspr play a role in strated by physiological and microanatomical maintenance of the segregation of these chan- studies, one can safely predict the existence of nels in the nodal membrane (Rios et al., 2003). elaborate mechanisms to manage and main- Here we present 3D representations of the tain the precise replacement of membrane node of Ranvier from young mice as obtained molecular machinery and to modulate the using serial section electron microscopic dynamic properties of the overall complex. tomography (EMT). The use of EMT has been In the early 1990s, (Ichimura and Ellisman, critical in recent years to understanding the 1991) published a three-dimensional (3D) structure and organization of large scale model of the fine structure of the nodal com- organelles such as mitochondria (Mannella et plex based on conventional and high voltage al., 1994; Nicastro et al., 2000; Perkins et al., electron microscopy of thin and semi-thick sec- 1997a), the Golgi apparatus (Ladinsky et al., tions and freeze fracture and deep-etching. The 1994; Marsh et al., 2001), actin networks in the model resulting from these structural studies leading edge of cells (Medalia et al., 2002), sep- contained transcellular structures across the tal pores (Martin et al., 2001) as well as deci- nodal gap and traversing the paranodal phering tissue level organization of structures glial–axonal junction. Both extracellular gap- in the nervous system (Harlow et al., 2001; crossing filaments and membrane–cytoskeletal Lenzi et al., 1999; Martone et al., 1999; Shoop linkers in the nodal axoplasm are joined to et al., 2002). Because of the size and complexity prominent membrane particles of the nodal of the node of Ranvier, the 3D structure can- axolemma. At the paranodal glial–axonal–junc not be inscribed in a single thick (0.5–1 µm) tion, the anchoring sites of other mem- section that is typically used with standard brane–cytoskeleton linkers are linear arrays of 300–400 keV electron microscopes. Instead, 16 nm particles.
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