Control of cortical slow oscillations and epileptiform discharges by photoswitchable type 1 muscarinic ligands (v1)

Acetylcholine is a key brain neurotransmitter, involved in processes such as wakening and cognitive functions. Its dysregulation has been linked to several neurological disorders, highlighting the relevance of cholinergic control in both basic research and clinical neurology. Here we modulated neuronal activity using cholinergic photopharmacology. We used selective type-1 muscarinic (M1) photoswitchable drugs, the agonist benzyl quinolone carboxylic acid–azo-iperoxo BAI and the antagonist cryptozepine-2, to evaluate their impact on cortical network activity by light-control. We confirmed M1 selectivity of BAI in cell cultures, to next demonstrate its ability to increase the frequency of slow oscillatory activity under light activation in cortical networks in vitro and in vivo. Additionally, we found that cryptozepine-2 suppressed M1-mediated epileptiform seizures through illumination. These results provide new insights on the M1-cholinergic effects in the cortex and open opportunities for light-based pharmacotherapies with high spatiotemporal resolution, enabling a precise modulation of brain activity in health and disease.