P322 Optogenetic inhibition of a hippocampal network model
Laila Weyn*1,2, Thomas Tarnaud1,2, Wout Joseph1, Robrecht Raedt2, Emmeric Tanghe1 1WAVES, Department of Information Technology (INTEC), Ghent University/IMEC, Technologiepark 126, 9000 Ghent, Belgium 24BRAIN, Department of Neurology, Institute for Neuroscience, Ghent University, Corneel Heymanslaan 10, 9000 Gent, Belgium *Email: laila.weyn@ugent.be
Introduction
Optogenetic inhibition of the hippocampus has emerged as a promising approach for suppressing seizures associated with temporal lobe epilepsy (TLE). Given the substantial size of the hippocampus and the inherent challenges of light propagation within the brain, understanding the influence of the volume and nature of the targeted region is crucial. To address these challenges, anin silicoapproach has been developed; allowing systematic exploration of the impact of different target regions on the effectiveness of optogenetic inhibition of seizure like activity in the hippocampus. Methods The hippocampal model described by Aussel et al. (2022) was modified and implemented in NEURON [1,2]. A photocurrent described by the double two-state opsin model was added to excitatory neurons of the Dentate Gyrus (DG_E) and Cornu Ammonis 1 (CA1_E) [3]. The impact of hippocampal sclerosis (HS) and mossy fiber sprouting (MFS) modelling [1] on excitability was assessed via an I/O curve of the CA1_E response to DG_E stimulation. Uncontrolled, self-sustaining, high frequency activity was induced in an epileptic network (MFS = 0.9) by reducing the inhibitory component of the EC theta input (see Fig. 1A). The effect of the target region on optogenetic inhibition was studied by varying the number of CA1_E and DG_E cells receiving a light pulse. Results The steeper slope of the population response curve suggests that increased MFS correlates with enhanced excitability. For HS, an inverse relationship is observed (Fig. 1B). When 100% of both DG_E and CA1_E regions is illuminated, all activity within the epileptic network is suppressed (Fig 1C.). Reducing the illumination of DG_E allows the network activity to return to theta activity. Notably, illumination of DG_E alone is insufficient to suppress high-frequency firing. These findings indicate that CA1 serves as a better target region for inhibiting hippocampal activity. Discussion The results regarding HS and MFS are in line with those observed by Aussel et al. (2022), though a different type of seizure-like activity is generated. Furthermore, the study shows the importance of selecting the appropriate stimulation region to effectively suppress hippocampal seizures. This preliminary investigation explores the capabilities of the network model but further investigation into the generation of seizure-like activity is necessary. Future work will aim for experimental validation of the model generated seizure-like activity and its response to optogenetic inhibition, with the ultimate aim of optimizing stimulation protocols.
Figure 1. A. Healthy and epileptic network response to EC theta current input and optogenetic modulation of CA1 and DG. B. Population response of CA1_E as a function of DG_E activity after stimulation at varying MFS and HS levels. C. Spike count in CA1_E and DG_E populations during optogenetic modulation (t = 1.75:2.25s) of varying amounts of neurons. Acknowledgements
