OXYTOCIN RECEPTORS IN NEURODEVELOPMENTAL DISORDERS: INNOVATIVE APPROACHES FOR THE QUANTIFICATION OF SOPRAMOLECULAR RECEPTOR COMPLEXES

In the brain, the oxytocinergic system is a key regulator of social behaviour. Oxytocin could therefore become a promising therapeutic molecule to treat behavioural alterations in neurodevelopmental disorders; however, in order to define its translational potential we need to understand more about the localization and signaling properties of its receptor (OTR) in the brain. The OTR is a G protein coupled receptor (GPCR) able to form homo or heterodimeric complexes with distinct pharmacological properties. Targeting GPCRs dimers in endogenous environments is often problematic: the techniques currently used to study them in native tissues can only prove molecular proximity between two protomers, not their actual dimerization. For these reasons, in my project I worked to develop new tools to study dimeric and monomeric OTRs in endogenous tissues. I characterized a series of bivalent ligands designed to pharmacologically target OTR homodimers, and started to develop an innovative “Nanoruler” technique to label OTR homodimers in native tissues. In parallel I also run an extensive autoradiographic mapping of the OTR in mouse brains, looking for changes of OTR levels in a mouse model of neurodevelopmental disorder (Magel2-KO). Through my work I already found important sex and genotype-induced effects on OTR expression in Magel2-KO mice, and I showed that in some cases a neonatal OT treatment (that can rescue some autistic traits of this model) modifies OTR levels in several regions. Once the Nanoruler technique is fully optimized we will compare its results with this mapping, to gather new important information about the dynamics of OTR distribution in mouse brain.