Anti-asthma drug Montelukast induces autistic behaviors via disrupting neuronal retinoic acid signaling [RNA-seq and Ribo-seq]

Globally, autism spectrum disorder (ASD) affects approximately 1.0-2.5% of human newborns, with non-genetic risk factors estimated to contribute to over 50% ASD cases through yet elusive mechanisms. Montelukast (MTK), a leukotriene receptor antagonist and FDA-approved anti-asthma drug, was found to potently disrupt retinoic acid (RA) signaling, and substantially increase the risk of ASD in humans when used during pregnancy or in early childhood, according to prospective and retrospective cohort studies. Both maternal and postnatal exposure to montelukast caused autistic-like behaviors in rat offspring. Montelukast also altered brain regional patterning through disrupting RA signaling in human cerebral organoids, similar to DEAB, an established inhibitor of RA-synthesizing ALDH1As. Mechanistically, montelukast was found to directly bind to retinoic acid receptor alpha (RARα) and impair RARα heterodimer formation to disrupt RA signaling. Altogether, this work highlighted not only the developmental origin of ASD, but the utmost importance in cautioned use of medicinal chemicals during maternity or early childhood to prevent psychiatric disorders, e.g. ASD.