Biology subjects

Weyn, L.

Publications and source records attributed to Weyn, L..

3 recordsLinked to original sources

bioRxiv2026

Seizure control via astrocyte targeted optogenetic extracellular potassium modulation: computational analysis of K+ vs non-selective cation-conducting opsins

Aims: Seizure generation has been strongly linked to the accumulation of extracellular potassium. As astrocytes play a key role in potassium homeostasis, astrocyte targeted optogenetic modulation of extracellular potassium has been proposed as a novel strategy for seizure control. The effectiveness of such modulation is expected to depend strongly on the ion selectivity of the employed opsin. This study aims to mechanistically compare potassium-selective (WiChR) and cation-conducting (ChR2-like, ChR2*) opsins for astrocyte targeted modulation of extracellular potassium, and to determine how astrocytic properties and stimulation parameters influence modulation efficacy. Methods: A conductance-based computational framework was used to model astrocyte-extracellular space interactions, incorporating ion-specific photocurrents, Na+/K+-ATPase activity, and gap junction-mediated coupling within the astrocytic syncytium. Systematic parameter sweeps were performed to evaluate the influence of ion selectivity, astrocytic parameters, and stimulation paradigms on potassium dynamics. Results: WiChR-based modulation consistently produced more effective and robust reductions in [K+]e than ChR2*, via direct K+ inward currents and reduced dependence on pump activity. In contrast, ChR2* primarily limited potassium accumulation rather than reversing it and exhibited greater sensitivity to parameter variations, particularly Na+/K+-ATPase activity. The effectiveness of astrocyte-targeted modulation was strongly dependent on syncytial integrity, with reduced gap junction coupling impairing potassium clearance. Optimal stimulation performance for WiChR was observed for a pulse repetition period of 20 ms, with outcomes determined by the interaction between opsin kinetics and stimulation parameters. Conclusions: These results demonstrate that activation of WiChR opsins in astrocytes can reduce extracellular potassium levels and thereby modulate neuronal excitability. Ion selectivity emerges as a key determinant of modulation efficacy at the astrocytic level, with potassium-selective opsins providing a more direct and reliable approach than non-selective cation-conducting alternatives. Together, these findings establish a mechanistic basis for optogenetic activation of astrocytic potassium buffering as a potential strategy for seizure suppression and other neurological disorders associated with potassium dysregulation.

neuroscience↗

bioRxiv2024

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

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 opsins opening and closing dynamics into its mathematical description. This model was also employed to determine that the impact of varying the opsins 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.

bioengineering↗

bioRxiv2023

Quantitative Analysis of the Optogenetic Excitability of CA1 Neurons

Optogenetics has emerged as a promising technique for modulating neuronal activity and holds potential for the treatment of neurological disorders such as temporal lobe epilepsy (TLE). However, clinical translation still faces many challenges. This in-silico study aims to enhance the understanding of optogenetic excitability in CA1 cells and to identify strategies for improving stimulation protocols. Employing state-of-the-art computational models, the optogenetic excitability of four CA1 cells, two pyramidal and two interneurons, expressing ChR2(H134R) is investigated. The results demonstrate that confining the opsin to specific neuronal membrane compartments significantly improves excitability. An improvement is also achieved by focusing the light beam on the most excitable cell region. Moreover, the perpendicular orientation of the optical fiber relative to the somato-dendritic axis yields superior results. Inter-cell variability is observed, highlighting the importance of considering neuron degeneracy when designing optogenetic tools. Opsin confinement to the basal dendrites of the pyramidal cells renders the neuron the most excitability. A global sensitivity analysis identified opsin location and expression level as having the greatest impact on simulation outcomes. The error reduction of simulation outcome due to coupling of neuron modeling with light propagation is shown. The results promote spatial confinement and increased opsin expression levels as important improvement strategies. On the other hand, uncertainties in these parameters limit precise determination of the irradiance thresholds. This study provides valuable insights on optogenetic excitability of CA1 cells useful for the development of improved optogenetic stimulation protocols for, for instance, TLE treatment.

neuroscience↗