Chronic oxytocin-driven alternative splicing of CRFR2α induces anxiety

Abstract

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 2a (CRFR2a) 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 (mCRFR2a) and soluble CRFR2a (sCRFR2a) in favor of the latter via ERK1/2-MEF2A signaling. Targeted manipulations of Crfr2a 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 sCRFR2a into the cerebrospinal fluid, with sCRFR2a levels positively correlating with anxiety-like behavior. Concluding, the dichotomy between anxiolytic mCRFR2a and anxiogenic sCRFR2a is the basis for the deleterious effects of chronic OXT on anxiety.

Altered PVN-to-CA2 hippocampal oxytocin pathway and reduced number of oxytocin-receptor expressing astrocytes in heart failure rats

“…Thus, we conclude that AVR-013 is a reliable and specific OTR antibody suited to study OTR levels in the rodent brain. In fact, this antibody has recently been used by other labs and validated using both peptide pre-incubation and knockdown approaches (34, 35).…”

“…We found that OTR immunoreactivity was essentially absent in OTR KO mice, thus confirming the specificity of the antibody. In fact, although this is a new batch of the OTR antibody, other labs have also successfully used the same (34, 35) or older batches (59), albeit without confirming its specificity via animal OTR KO models. We used this antibody to investigate neuronal and astrocytic OTR expression and obtained results ( Figure 4 and 5 ) consistent with our data obtained via RNAScope ( Figure 5 and 6 ), again confirming the efficacy and specificity of the antibody.…”

Interactions between theκopioid system, corticotropin-releasing hormone and oxytocin in partner loss

“…OT has one known receptor, a G-coupled receptor that can have differing effects depending on which secondary messaging system it activates [65]. OT also has numerous interactions with hormones within the hypothalamic–pituitary–adrenal axis, including CRH and glucocorticoids [66,67]. Interactions between OT and the µ opioid system have been studied as well, both in the context of pregnancy in rats [68] and in social attention in primates [69].…”

Oxytocin and vasopressin: Signalling, behavioural modulation and potential therapeutic effects

“…For instance, acute OT negatively regulates transcription of the crf gene (Jurek et al, 2015). On the other hand, chronic OT treatment increases phosphorylation of myocyte enhancing factor 2A (MEF2A), a transcription factor that induces alternative splicing of the crf2a gene, leading to the formation of a soluble form sCRF2α (Winter et al, 2020). Indeed, studies have shown a positive correlation between sCRF2α and anxiety-like behaviour (Jurek & Meyer, 2020).…”