Seizure control via astrocyte targeted optogenetic extracellular potassium modulation: computational analysis of K + vs non-selective cation conducting opsins
Year: 2026
Type: preprint
Abstract: ABSTRACT 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. AUTHOR SUMMARY Excessive accumulation of potassium in the extracellular space is thought to contribute to seizures by increasing neuronal excitability. Astrocytes play a central role in regulating extracellular potassium levels and have therefore emerged as promising targets for therapeutic intervention. Optogenetic tools enable light-controlled ion currents to be introduced into astrocytes, potentially enabling direct modulation of potassium homeostasis. Previous experimental work has shown that astrocytic modulation via non-selective cation channels can reduce seizure activity, but the recent development of potassium-selective opsins raises the possibility of directly controlling astrocyte-mediated potassium currents. However, it remains unclear how the ion selectivity of these currents influences their ability to regulate extracellular potassium. Using a computational model of astrocyte potassium homeostasis, we compared the effects of activating a potassium-selective opsin (WiChR) with a non-selective cation-conducting opsin (ChR2-like). We found that potassium-selective modulation produces a larger and more robust reduction in extracellular potassium because potassium currents directly contribute to potassium clearance. In contrast, ChR2-like modulation relies more strongly on indirect mechanisms, including sodium accumulation and enhanced pump activity, making its effectiveness more sensitive to cellular properties and network conditions. We also identified astrocytic gap-junction coupling as a key determinant of successful potassium regulation. These findings identify potassium-selective opsins as a promising tool for controlling extracellular potassium dynamics. More broadly, this study provides mechanistic insight into how astrocytes regulate brain excitability and offers guidance for the development of future optogenetic strategies targeting disorders associated with disrupted potassium homeostasis.
Institutions: Ghent University, IMEC
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Award: G7475919089
OpenAlex ID: W7214648431