Control of cortical slow oscillations and epileptiform discharges with photoswitchable type 1 muscarinic ligands

Acetylcholine and the cholinergic system are crucial to brain function, including functions such as consciousness and cognition. Dysregulation of this system is implicated in the pathophysiology of neurological conditions such as Alzheimer's disease. For this reason, cholinergic neuromodulation is relevant in both basic neuroscience and clinical neurology. In this study, we used photopharmacology to modulate neuronal activity using the novel selective type-1 muscarinic (M1) photoswitchable drugs: the agonist benzyl quinolone carboxylic acid-azo-iperoxo (BAI) and the antagonist cryptozepine-2. Our aim was to investigate the control over these cholinergic receptors using light and to investigate the effects of these drugs on physiological spontaneous slow waves and on epileptic activity in the cerebral cortex. First, we used transfected HEK cell cultures and demonstrated BAI's preferential activation of M1 muscarinic acetylcholine receptors (mAChRs) compared with M2 mAChRs. Next, we found that white-light illumination of BAI increased the frequency of spontaneous slow-wave activity in brain cortical networks of both active slices and anesthetized mice, through M1-mAChRs activation. Illumination of cryptozepine-2 with UV light effectively suppressed not only the muscarinic-induced increase in slow-wave frequency, but also muscarinic-induced epileptiform discharges. These findings not only shed light on the role of M1 acetylcholine receptors in the cortical network dynamics but also lay the groundwork for developing advanced light-based pharmacological therapies. Photopharmacology offers the potential for high-precision spatiotemporal control of brain networks with high pharmacological specificity in both healthy and pathological conditions.