Research Highlight

NCMIR scientists in combination with Salk Institute is the first to model axonal conduction to include a more realistic three-dimensional geometry of cellular microdomains.

3D reconstruction of cellular membrane systems in the mouse myocardium by EM tomography. (A) A stereoscopic sectional view of a volume reconstruction (size, 3.8x5.7x0.43 µm3; voxel size, 1.42 nmx1.42 nmx1.42 nm; total, 3.2 billion voxels). The upper face of the volume represents the two-dimensional (2D) image of a computed 1.42 nm slice. (B) Higher magnification view of one of the dyads in A (indicated by the arrow in A). (C) T-tubules (green), jSR (yellow) and dyadic cleft (white) were segmented as shown. The dyadic cleft is defined as a space between the opposing membranes of a jSR containing electron-dense contents (i.e. junctional granules) and a T-tubule. RyR feet are identified in the space; however, they do not always fill the cleft. The lateral border of the cleft is determined where the contours of the jSR and T-tubule membranes start to dissociate. (D) The 3D mesh models of polymorphic T-tubules (green), jSR (yellow) and mitochondria (magenta) are shown with the 2D image of a middle slice of the tomographic volume. (E) Sectional view of another volume that crosscuts most of the myofilaments. (F) The 3D mesh models of T-tubules, jSR and mitochondria in this volume. Scale bars: 1 µm in A,D; 200 nm in B,C; 500 nm in E,F.

December 2008 — Electrochemical signal transduction in cells depends on the subcellular organization of structural components, as well as on the electric profiles created by electrodiffusion of ions. Electrochemical diffusion is particularly important in nerve impulse transduction. With respect to neuronal cells and even at a higher systems level such as brain tissue, a fundamental question arises: how can seemingly similar cells such as neurons have such different electrophysiological properties from one another? To better understand the electrophysiological properties of cell components, structures need to be accurately modeled in three-dimensions, with both intra- and extracellular details, elucidating factors influencing the accumulation and depletion of ions, as well as the physiological details that predict how ions interact with each other and their surroundings. The impact of intra- and extracellular structure on the physiology of ion channels and pumps is a question that needs to be addressed in order to understand how axons in various species or even within the same tissue with similar channel expression transmit electrical signals differently.

A recently published paper by researchers Courtney Lopreore, Tom Bartol, Jay Coggan, Dan Keller and Terry Sejnowski at the Salk in combination with NCMIR scientists Mark Ellisman and Gina Sosinsky is the first to model axonal conduction to include a more realistic three-dimensional geometry of cellular microdomains, as well as the merging of two spatial and temporal scales to study signal transmission: the nanometer/picosecond space/time frame of ions interacting with each other and the edges of the membrane, and the multiple micrometers/milliseconds space/time frame of propagating action potentials. This algorithm is the first to incorporate three-dimensional ionic electrodiffusion, with the mathematical challenges of modeling multi-materials with discontinuous boundaries. It documents how at smaller clusters of voltage-gated ion channels, the 3D electrodiffusion predictions diverge from cable model predictions and show a broadening of the action potential, indicating a significant effect due to each channel's own local electric field.

Related Publications

Lopreore, C. L., T. M. Bartol, J. S. Coggan, D. X. Keller, G. E. Sosinsky, M. H. Ellisman, and T. J. Sejnowski. 2008. Computational modeling of three-dimensional electrodiffusion in biological systems: application to the node of Ranvier. Biophys. J. 95:2624-2635.