The extracellular matrix protein reelin, named after the reeler-mutant mouse, exerts a multitude of key functions in both the developing and adult brains of mammals. In addition to the well-studied effect of reelin on the migration of neuronal cells during embryonic development, several studies have demonstrated an effect of reelin on neuronal signaling in the mature brain. By modulating both excitatory glutamatergic and inhibitory GABAergic neuronal signaling, reelin affects central neurophysiological processes such as learning and memory formation. We aim to further investigate reelin-induced changes of the neuronal signal transmission focusing on the cholinergic system. Although cholinergic projections modulate neurons in various brain regions, the impact of reelin on the cholinergic system has so far not been examined. By using the calcium imaging technique on primary neurons, cell lines and rodent brain slices we investigated the effect of reelin on neuronal acetylcholine-induced calcium signals. Furthermore, we analyzed the underlying molecular mechanisms of action in more detail by using mass spectroscopy, epigenetic profiling, western blotting and immunofluorescent staining.Our preliminary results show that reelin reduces acetylcholine-induced calcium signals in a receptor-specific manner. Furthermore, reelin increases the nuclear distribution of specific transcription factors, alters the level of different epigenetic protein modifications and modulates the proteome of the treated neurons. Identifying the underlying molecular mechanisms will complement our knowledge of reelin’s action in both the developing and the mature brain and contribute to a better understanding of the interplay between posttranslational protein modifications, their intracellular pathways and neuronal signaling processes.