Modeling the dynamics of light-driven microbial opsin ChrimsonR

Abstract

Purpose : Optogenetics is increasingly used to externally drive neural behavior both in research and medical applications. Both fields need to control precisely the behavior of the neurons expressing the light-sensitive ion channels, and therefore need precise models describing the evolution of the conductance of the channels when submitted to an arbitrary light command. We developed a dual approach combining theoretical work and simulation-based parameter estimation based on patch-clamp recordings of HEK cells expressing the ChrimsonR channel to model the gating dynamics of the channel.

Methods : ChrimsonR channels were expressed into HEK cells which were then used in voltage-clamp experiments where the cells were submitted to light commands involving a wide range of light intensities and time scales for each cell. Markov kinetic models were used to describe the different conformations of the molecule and the transitions dynamics between the states. Using theoretical results on Markov kinetic models, we were able to set the lower bound to the number of states required to explain the data to five. Further theoretical results brought a number of constraints on the possible transitions from one state to the other. These theoretical results served as a basis for a simulation-based search for the correct model and an estimation of its parameters. The search was organized along a sequence of models with increasing complexity and capturing additional features of the data at each step of the process.

Results : Theoretical considerations showed that at least five states, including two conductive states, were necessary to explain elementary observations and statistical analyzes. A preliminary set of models with limited numbers of states have been set to model independently the behavior of the channels for different time scales ranging from a about two milliseconds to several minutes (underlying a slow adaptation behavior occurring when the channel is stimulated with high light intensity).

Conclusions : This preliminary study lays the groundwork for an integrated Markov kinetic model capturing the relationship between light stimulation and ChrimsonR conductance at multiple time scales.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.