The ADCY1-mediated cAMP signaling pathway mediates functional effects of montelukast treatment in brain organoids.

Montelukast (MTK) is a drug widely used for treating allergic rhinitis and asthma. However, severe neuropsychiatric adverse events related to MTK have been reported, with limited understanding of the underlying mechanisms. Here we leveraged human forebrain organoids (hFOs) and showed that MTK exposure in hFOs downregulated the expression of genes associated with multiple neuronal functions and neuropsychiatric disorders. The following integrative analysis highlighted adenylate cyclase 1 (ADCY1), a main regulator of the cAMP signaling pathway, as a hub gene mediating the functional effects of MTK exposure. We also showed that MTK exposure resulted in a reduction of cAMP and neuroactivities, and caused neural maturation defects. These cellular phenotypes could be recapitulated by treating hFOs with ST034307, a selective ADCY1 inhibitor, or partially rescued by ADCY1 overexpression in hFOs. Together, this study underscored that MTK exposure caused neuropsychiatric effects through inhibiting the ADCY1-mediated cAMP signaling pathway.