Attenuation of oxytocin and serotonin 2A receptor signaling through novel heteroreceptor formation

The oxytocin receptor (OTR) and the 5-hydroxytryptamine 2A receptor (5-HTR2A) are expressed in similar brain regions modulating central pathways critical for social and cognition-related behaviors. Signaling crosstalk between their endogenous ligands, oxytocin (OT) and serotonin (5-hydroxytryptamine, 5-HT), highlights the complex interplay between these two neurotransmitter systems and may be indicative of the formation of heteroreceptor complexes with subsequent downstream signaling changes. In this study, we assess the possible formation of OTR-5HTR2A heteromers in living cells and the functional downstream consequences of this receptor–receptor interaction. First, we demonstrated the existence of a physical interaction between the OTR and 5-HTR2Ain vitro, using a flow cytometry-based FRET approach and confocal microscopy. Furthermore, we investigated the formation of this specific heteroreceptor complex ex vivo in the brain sections using the Proximity Ligation Assay (PLA). The OTR-5HTR2A heteroreceptor complexes were identified in limbic regions (including hippocampus, cingulate cortex, and nucleus accumbens), key regions associated with cognition and social-related behaviors. Next, functional cellular-based assays to assess the OTR-5HTR2A downstream signaling crosstalk showed a reduction in potency and efficacy of OT and OTR synthetic agonists, carbetocin and WAY267464, on OTR-mediated Gαq signaling. Similarly, the activation of 5-HTR2A by the endogenous agonist, 5-HT, also revealed attenuation in Gαq-mediated signaling. Finally, altered receptor trafficking within the cell was demonstrated, indicative of cotrafficking of the OTR/5-HTR2A pair. Overall, these results constitute a novel mechanism of specific interaction between the OT and 5-HT neurotransmitters via OTR-5HTR2A heteroreceptor formation and provide potential new therapeutic strategies in the treatment of social and cognition-related diseases

Molecular, biochemical and behavioural evidence for a novel oxytocin receptor and serotonin 2C receptor heterocomplex

The complexity of oxytocin-mediated functions is strongly associated with its modulatory effects on other neurotransmission systems, including the serotonin (5-hydroxytryptamine, 5-HT) system. Signalling between oxytocin (OT) and 5-HT has been demonstrated during neurodevelopment and in the regulation of specific emotion-based behaviours. It is suggested that crosstalk between neurotransmitters is driven by interaction between their specific receptors, particularly the oxytocin receptor (OTR) and the 5-hydroxytryptamine 2C receptor (5-HTR2C), but evidence for this and the downstream signalling consequences that follow are lacking. Considering the overlapping central expression profiles and shared involvement of OTR and 5-HTR2C in certain endocrine functions and behaviours, including eating behaviour, social interaction and locomotor activity, we investigated the existence of functionally active OTR/5-HTR2C heterocomplexes. Here, we demonstrate evidence for a potential physical interaction between OTR and 5-HTR2C in vitro in a cellular expression system using flow cytometry-based FRET (fcFRET). We could recapitulate this finding under endogenous expression levels of both receptors via in silico analysis of single cell transcriptomic data and ex vivo proximity ligation assay (PLA). Next, we show that co-expression of the OTR/5-HTR2C pair resulted in a significant depletion of OTR-mediated G alpha q-signalling and significant changes in receptor trafficking. Of note, attenuation of OTR-mediated downstream signalling was restored following pharmacological blockade of the 5-HTR2C. Finally, we demonstrated a functional relevance of this novel heterocomplex, in vivo, as 5-HTR2C antagonism increased OT-mediated hypoactivity in mice. Overall, we provide compelling evidence for the formation of functionally active OTR/5-HTR2C heterocomplexes, adding another level of complexity to OTR and 5-HTR2C signalling functionality.This article is part of the special issue on Neuropeptides

La fin du Néolithique et les débuts de la métallurgie en Languedoc central. Les habitats de la colline du Puech Haut à Paulhan, HéraultRecherches en Archéologie Préventive, 3

Publié avec le concours de la Direction Régionale des Affaires Culturelles de Languedoc-Roussillon (Ministère de la Culture et de la Communication)International audienceMis au jour sur le tracé de l'autoroute A75, entre Clermont-l'Hérault et Pézenas, les habitats néolithiques de la colline du Puech Haut (Paulhan-Hérault) ont fait l'objet, en 1998, d'une fouille archéologique préventive. Occupé de la fin du 4ème millénaire jusqu'aux derniers siècles du 3ème millénaire avant J.-C., cet établissement se caractérise par la succession, en un même lieu, de plusieurs enceintes auxquelles sont associés des aménagements domestiques. La première phase d'occupation, datée des derniers siècles du 4ème millénaire avant notre ère, correspond à un habitat ceinturé d'une simple palissade. La seconde phase (début du 3ème millénaire avant notre ère) se définit par le creusement d'un fossé sur le tracé même de l'enceinte primitive. Des bastions semi-circulaires flanqués d'une levée de terre témoignent de l'aspect défensif de l'édifice. On observe alors une densification de l'habitat qui se traduit par une augmentation du nombre et de l'emprise des structures domestiques (silos, fosses, caves...). La dernière grande étape d'occupation, datée de la seconde moitié du 3ème millénaire avant notre ère, est contemporaine du Fontbouisse. Elle comporte une enceinte sensiblement plus grande, dont les fossés sont localement bordés de murs de pierre sèche : le statut de fortification est alors clairement affirmé. Sur les ruines du démantèlement de ce rempart, on a pu ponctuellement retrouver des dépôts, localisés au sommet des fossés, de céramiques campaniformes