SUMMARY Recently, oxytocin (OXT) has generated considerable interest as potential treatment for psychiatric disorders, including general anxiety disorder or autism spectrum disorder. Therefore, knowledge on the involved molecular processes downstream of OXT receptor (OXTR) activation is indispensable. We reveal that alternative splicing of corticotropin releasing factor receptor 2α (CRFR2α) parallels increased anxiety-like behavior following chronic OXT treatment, contrasting the well-known anxiolysis of acute OXT. In detail, chronic OXT shifts the splicing ratio between membrane-bound (mCRFR2α) and soluble CRFR2α (sCRFR2α) in favor of the latter via ERK1/2-MEF2A signaling. Targeted manipulations of Crfr2α splicing mimic the effect of chronic OXT, confirming its role in the regulation of anxiety-like behavior. Furthermore, chronic OXT triggers cytoplasmic distribution and extracellular release of sCRFR2α into the cerebrospinal fluid, with sCRFR2α levels positively correlating with anxiety-like behavior. Concluding, the dichotomy between anxiolytic mCRFR2α and anxiogenic sCRFR2α is the basis for the deleterious effects of chronic OXT on anxiety. Graphical Abstract

Chronic oxytocin-driven alternative splicing of CRFR2α induces anxiety