Modeling Drosophila motoneurons to examine the functional effect of Na channel splice variants

Abstract

Event Abstract Back to Event Modeling Drosophila motoneurons to examine the functional effect of Na channel splice variants Cengiz Gunay1*, Logesh Dharmar1, Fred Sieling1, Richard Marley2, Wei-Hsiang Lin2, Richard A. Baines2 and Astrid A. Prinz1 1 Emory University, Biology Dep, United States 2 University of Manchester, Life Sciences, United Kingdom Neurons have diverse electrophysiological characteristics controlled by voltage-gated ion channels. It is not known how much of the diversity of neuronal activity is caused by differential channel gene expression as opposed to alternate splicing of these genes. The contribution of alternate splicing to neural activity and therefore neuronal function can be addressed more easily in invertebrates because of their smaller genome. Specifically, the fruitfly Drosophila melanogaster represents a very powerful molecular genetic model system that has been instrumental for our understanding of early development of the nervous system. Recently in Drosophila, several voltage-gated sodium channel (DmNav) splice variants have been identified [1]. However, the expression of DmNav splice variants cannot yet be controlled in Drosophila, preventing the analysis of their effect on neuronal function. Instead, splice variants can be expressed in the oocytes of the South African clawed frog Xenopus Laevis. The expression of these channels in Xenopus oocytes allows the electrophysiological characterization and the construction of computational ion channel models. If these models are built with sufficient detail, the functional effect of the splice variants on neuronal activity thus can be analyzed. As a first step in this task, we build a full computational model of the Drosophila motoneuron, which, to our knowledge, has not been accomplished before. To build this model, we combine channel data recorded from Drosophila and oocytes. In the oocytes, recordings show a space clamp problem because of the oocytes' large size, which is required for expressing DmNav splice variants. We address this problem with a spatial model of leak current in the oocyte. We present solutions to several obstacles in modeling fast kinetics of DmNav channels and also putting them together in a full model of a Drosophila motoneuron.