Ionic channel changes in glaucomatous retinal ganglion cells: multicompartment modeling Matias I. Maturana 1,2 , Andrew Turpin 3 , Allison M. McKendrick 4 , Tatiana Kameneva 1 Abstract— This research takes a step towards discover- ing underlying ionic channel changes in the glaucomatous ganglion cells. Glaucoma is characterized by a gradual death of retinal ganglion cells. In this paper, we propose a hypothesis that the ionic channel concentrations change during the progression of glaucoma. We use computer simulation of a multi-compartment morphologically cor- rect model of a mouse retinal ganglion cell to verify our hypothesis. Using published experimental data, we alter the morphology of healthy ganglion cells to replicate glauco- matous cells. Our results suggest that in glaucomatous cell, the sodium channel concentration decreases in the soma by 30% and by 60% in the dendrites, calcium channel concentration decreases by 10% in all compartments, and leak channel concentration increases by 40% in the soma and by 100% in the dendrites. I. INTRODUCTION Glaucoma, a chronic neurodegenerative disease of retinal ganglion cells (RGCs), is the second leading cause of irreversible blindness worldwide. It is estimated that 79.6 million of people worldwide will develop glaucoma by 2020, exacerbated by our ageing society [17]. Glaucoma is a disease of the progressive optic neuropathy which is characterized by the progressive death of RGCs leading to morphological changes in the optic nerve. The exact pathogenesis of glaucoma is not clear. Current understanding of the ionic channels neuropa- thy in glaucomatous eyes is poor. Experimental data shows that calcium and sodium channel dynamics con- tribute to the ischemic axon injury; calcium deregulation reduces the capacity for mitochondria to buffer calcium from the cell leading to the reduced clearance of the intracellular calcium ions from the intracellular space; the entry of the extracellular calcium ions into the axo- plasm plays an important role in the axon degeneration; sodium channel blockers contribute to the recovery of the optic nerve compound potentials; and that calcium channel blockers may or may not protect optic nerves from anoxia [4], [16], [21], [22]. 1 NeuroEngineering Laboratory, Department of Electrical Elec- tronic Engineering, The University of Melbourne, Australia. 2 National Vision Research Institute, Australian College of Optometry, Australia. 3 Department of Computing and Information Systems, The University of Melbourne, Australia. 4 Department of Optometry and Vision Sci- ence, The University of Melbourne, Australia. *tkam@unimelb.edu.au Histology shows that the morphology of the ganglion cells alter prior to the neurons death due to glaucoma. The ganglion cells in glaucomatous eyes have smaller soma, the structure of their dendritic tree is less complex and their dendrites are shorter compared to healthy cells [23]. Currently, it is not clear how these morphological changes affect human vision prior to cell death. It is critically important to the future development of neuroprotective strategies for glaucoma to understand the effects of cellular alterations prior to cell death. This project aims to understand the ionic channel changes in glaucomatous ganglion cells. The results of this study may have implications for the development of tests for cellular abnormalities in human early glaucoma. The initiation of the disease and its progression can be studied using mathematical modelling and computer simulation. In many cases, computer simulations have many advantages over in vitro and in vivo experiments and psychophysical studies, including relative simplicity to manipulate parameters and draw conclusions without the need for multiple repetitions of an experiment. In this project, we use computer simulations as a tool to study intrinsic electrophysiology of glaucomatous ganglion cells. II. METHODS Numerical simulations of a multicompartment model of a mouse RGC were carried out in NEURON envi- ronment and the data were analyzed in Matlab [8]. The cell’s compartments representing the dendrites, soma and axon were taken as cylinders of variable diameter and length. The ionic channel concentrations varied among different compartments. The cell’s morphology was taken from the NeuroMorpho database (Chalupa 189 cell) [2]. The membrane potential dynamics were simulated us- ing Hodgkin-Huxley-type equations, similar to [6], and included sodium (I Na ), calcium (I Ca ), delayed rectifier potassium (I K ), A-type (I K,A ), Ca-activated potassium (I Ca ), and leak (I L ), currents: C m dV dt = I Na + I Ca + I K + I K,A + I K(Ca) + I L + I stim , (1) 978-1-4244-7929-0/14/$26.00 ©2014 IEEE 4535