Unraveling endocannabinoid signaling disruption in a preclinical model of neurodevelopmental disorders

The search for transformative medicines has continuously uncovered select diseases associated with the disruption of the endocannabinoid (eCB) signaling system in the brain and emphasized the therapeutic value of small molecules that rescue this signaling system. In this issue of JCI, Wang et al. report that genetic disruption of PPP2R1A function in mouse forebrain, a preclinical mouse model of neurodevelopmental disorders, resulted in pronounced impairment of eCB signaling. Notably, small-molecule inhibitors of eCB inactivation rescued both eCB signaling and cognitive dysfunction in this model, providing a solid foundation to move such transformative therapeutic approaches based on targeting eCB signaling toward human clinical trial testing.