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

Abstract

Optogenetic inhibition of excitatory populations has been suggested as a novel technique for the treatment of refractory epilepsy. While this approach holds significant potential, achieving seizure suppression in animal models using optogenetics has proven challenging. This difficulty can be attributed to a suboptimal stimulation method that involves numerous complex variables. To provide insight into these parameters, the behavior of the chloride conducting opsin, GtACR2, was fitted to a mathematical description and combined with a conductance-based model of a pyramidal CA1 neuron. The resulting model was adapted to add the ability to study potassium conducting opsins and used to demonstrate that the effect of an optogenetic modulation setup is highly dependent on its parameters and the physiological conditions of the neuronal environment. Stronger inhibition is observed at higher pulse repetition frequencies and duty cycles. Furthermore, potassium conducting opsins were shown to be more stable in use than chloride conducting ones. The dependence of these observations on the opsin model fit was found to be negligible. To determine this, a simplified model (22OMs) is proposed that permits easy implementation of the experimentally derived parameters describing the opsin's opening and closing dynamics into its mathematical description. This model was also employed to determine that the impact of varying the opsin's dynamics is insignificant when the opening and closing time constants are altered by a factor between 0.5 and 2. Consequently, this study provides insights into the stimulation and physiological parameters influencing the outcome of an optogenetic inhibition approach and offers a new tool that will facilitate future research into the development of an improved optogenetic modulation protocol for seizure suppression.