Computational analysis of optogenetic inhibition of CA1 neurons using a data-efficient and interpretable potassium and chloride conducting opsin model

Abstract

Objective. Optogenetic inhibition of excitatory neuronal populations has emerged as a potential strategy for the treatment of refractory epilepsy. However, achieving effective seizure suppression in animal models using optogenetic techniques has proven challenging. This difficulty can be attributed to a suboptimal stimulation method that involves numerous complex variables. This study aims to examine how various stimulation parameters and opsin characteristics influence the efficacy of optogenetic inhibition protocols. Additionally, a new opsin model is introduced that permits easy implementation of the experimentally derived parameters describing the opsin’s opening and closing dynamics. Approach. The mathematical description of a chloride and potassium conducting opsin was combined with a conductance-based model of a pyramidal CA1 neuron. Simulations with varying parameters were conducted to explore the effects of the stimulation paradigm and the neuronal environment on inhibition. A simplified, adaptable opsin model was used to test the robustness of these results and explore the impact of variations in opsin characteristics. Main results. Stronger inhibition was achieved with higher illumination intensities, pulse repetition frequencies, and duty cycles. Potassium conducting opsins were found to be more stable than chloride conducting ones. These findings were independent of the opsin’s parameters. Additionally, changes in the opsin’s dynamics had negligible impact when the opening and closing time constants were varied by factors between 0.5 and 2. Significance. This study provides key insights into the stimulation and physiological parameters that affect optogenetic inhibition. The findings highlight the importance of choosing the right stimulation protocol and opsin for optimizing optogenetic strategies. The newly developed opsin model also offers a new, valuable tool that will facilitate future research into the development of an improved optogenetic modulation protocol for seizure suppression.