5-HT1A and 5-HT2B receptor interaction and co-clustering regulates serotonergic neuron excitability

Many psychiatric diseases including depression, schizophrenia and anxiety have been associated with serotonin (5-HT) signaling dysfunction. We previously showed that the 5-HT2B receptor was expressed by 5-HT neurons together with 5-HT1A receptors. Whether 5-HT2B and 5-HT1A receptors interact and the functional consequences of this putative interaction are unknown. Using co-immunoprecipitation, BRET, confocal and super-resolution microscopy in hippocampal cultured neurons, we found that 5-HT1A and 5-HT2B receptors form heterodimers and co-cluster at the surface of dendrites. The 5-HT2B receptor cell-surface expression was reduced and the clusters were redistributed upon expression of the 5-HT1A receptor suggesting functional interactions between the two receptors. Furthermore, the expression of the 5-HT2B receptor prevented the 5-HT1A receptor agonist-induced internalization, whereas the presence of the 5-HT1A receptor mimicked the effect of the stimulation of the 5-HT2B receptor on its surface expression. These data demonstrate a direct crosstalk between 5-HT1A and 5-HT2B receptors. To investigate the functional impact of this interaction in-vivo, we assessed 5-HT neuron excitability from mice lacking 5-HT2B receptors in 5-HT neurons. We found upon 5-HT1A receptor stimulation that the firing activity of 5-HT neurons was increased in the absence of 5-HT2B receptors and decreased in its presence through regulation of SK channels, thus demonstrating the functional significance of these receptor interactions. ### Competing Interest Statement The authors have declared no competing interest.