Photopharmacological Cholinergic Modulation of Cortical Activity in Human Brain Slices

Background/Objectives: Understanding the unique properties of human neurons is crucial for advancing knowledge of brain function and facilitating clinical translation. This study explores the use of photopharmacology, specifically a photoswitchable ligand, Phthalimide-Azo-Iperoxo (PAI), to modulate cortical activity in human brain slices. Methods: Human cortical tissue was obtained from patients undergoing resective neurosurgery for pharmacoresistant epilepsy. The inactive cis isomer of PAI (200 nM) was bath-applied to brain slices exhibiting slow-oscillatory activity, producing no effect on the ongoing network activity. Subsequent illumination of the slices with white light induced photoconversion to trans-PAI, the active form of the compound. Results: Photoactivation of PAI selectively activated M₂ muscarinic acetylcholine receptors, resulting in a significant increase in oscillatory frequency accompanied by reductions in both Up-state and Down-state durations. Conclusions: In this proof-of-concept study, our findings provide preliminary evidence that photopharmacology can selectively modulate slow oscillations in human cortical circuits, highlighting its potential as a tool for investigating human cortical dynamics. By extending observations previously made in animal models to human tissue, this work establishes the feasibility of photopharmacological modulation in human cortical tissue and provides a foundation for future translational research.