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

Amina Benhadda (1) , Célia Delhaye (1) , Imane Moutkine (1) , Xavier Marques (1) , Marion Russeau (1) , Corentin Le Magueresse (1) , Anne Roumier (1) , Sabine Lévi (1) , Luc Maroteaux (1)

1 IFM - Inserm U1270 - SU - Institut du Fer à Moulin

Many psychiatric diseases have been associated with serotonin (5-HT) neuron dysfunction. The firing of 5-HT neurons is known to be under 5-HT1A receptormediated 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-HT1A and 5-HT2B receptors can form heterodimers and co-cluster at the plasma membrane of dendrites. Selective agonist stimulation of coexpressed 5-HT1A and 5-HT2B receptors prevents 5-HT1A receptor internalization and increases 5-HT2B receptor membrane clustering. Current clamp recordings of 5-HT neurons revealed that 5-HT1A receptor stimulation of acute slices from mice lacking 5-HT2B receptors in 5-HT neurons increased their firing activity trough Ca2+-activated potassium channel inhibition compared to 5-HT neurons from control mice. This work supports the hypothesis that the relative expression of 5-HT1A and 5-HT2B receptors tunes the neuronal excitability of serotonergic neurons through potassium channel regulation.

Keywords: Cell biology; Neuroscience

Domains: Life Sciences [q-bio]

Amina Benhadda, Célia Delhaye, Imane Moutkine, Xavier Marques, Marion Russeau, et al.. 5-HT1A and 5-HT2B receptor interaction and co-clustering regulate serotonergic neuron excitability. iScience, 2023, 26 (8), pp.107401. ⟨10.1016/j.isci.2023.107401⟩. ⟨hal-04196168⟩