Chronic oxytocin-driven alternative splicing of CRFR2α induces anxiety

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 2 (CRFR2) 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 (mCRFR2) and soluble CRFR2 (sCRFR2) in favor of the latter via ERK1/2-MEF2A signaling. Targeted manipulations of Crfr2 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 sCRFR2 into the cerebrospinal fluid, with sCRFR2 levels positively correlating with anxiety-like behavior. Concluding, the dichotomy between anxiolytic mCRFR2 and anxiogenic sCRFR2 is the basis for the deleterious effects of chronic OXT on anxiety. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/255844v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1b50691org.highwire.dtl.DTLVardef@1c22efborg.highwire.dtl.DTLVardef@19a772eorg.highwire.dtl.DTLVardef@69af7_HPS_FORMAT_FIGEXP M_FIG C_FIG