5-HT and 5-HT receptor interaction and co-clustering regulate serotonergic neuron excitability.

Many psychiatric diseases have been associated with serotonin (5-HT) neuron dysfunction. The firing of 5-HT neurons is known to be under 5-HT receptor-mediated autoinhibition, but functional consequences of coexpressed receptors are unknown. Using co-immunoprecipitation, BRET, confocal, and super-resolution microscopy in hippocampal and 5-HT neurons, we present evidence that 5-HT and 5-HT receptors can form heterodimers and co-cluster at the plasma membrane of dendrites. Selective agonist stimulation of coexpressed 5-HT and 5-HT receptors prevents 5-HT receptor internalization and increases 5-HT receptor membrane clustering. Current clamp recordings of 5-HT neurons revealed that 5-HT receptor stimulation of acute slices from mice lacking 5-HT receptors in 5-HT neurons increased their firing activity trough Ca-activated potassium channel inhibition compared to 5-HT neurons from control mice. This work supports the hypothesis that the relative expression of 5-HT and 5-HT receptors tunes the neuronal excitability of serotonergic neurons through potassium channel regulation.