5-HT1Aand 5-HT2Breceptor interaction and co-clustering regulates serotonergic neuron excitability

Abstract

AbstractMany psychiatric diseases including depression, schizophrenia and anxiety have been associated with serotonin (5-HT) neuron dysfunction. Pacemaker-like firing of raphe 5-HT neurons was proposed to be under unique 5-HT1Areceptor-mediated autoinhibition. We previously showed that 5-HT2Breceptors were expressed by 5-HT neurons together with 5-HT1Areceptors. However, functional consequences on 5-HT neurons of putative interaction between these receptors are unknown. Using co-immunoprecipitation, BRET, confocal and super-resolution microscopy in hippocampal and 5-HT neurons, we present converging evidence that 5-HT1Aand 5-HT2Breceptors can form heterodimers and co-cluster at the surface of dendrites. 5-HT2Breceptor clusters were redistributed upon 5-HT1Areceptor expression supporting functional interactions between the two receptors. Furthermore, 5-HT2Breceptor expression prevented agonist-induced internalization of 5-HT1Areceptors, whereas 5-HT1Areceptors mimicked the clustering effect of 5-HT2Breceptor stimulation on its surface expression. The functional impact of this interactionin-vivowas assessed by recording 5-HT neuron excitability from mice lacking 5-HT2Breceptors in 5-HT neurons. Upon 5-HT1Areceptor stimulation, the firing activity of 5-HT neurons was increased in the absence of 5-HT2Breceptors and decreased in their presence through regulation of SK channels, thus demonstrating functional output of this interaction in controlling 5-HT neuron firing activity.