Positive regulation of raphe serotonin neurons by serotonin 2B receptors

• DOI: 10.1038/s41386-018-0013-0
• Publication Date: 2018-02-05T21:47:15Z
• Authors: Arnauld Belmer; Emily Quentin; Silvina L. Diaz; Bruno P. Guiard; Sebastian P. Fern...; Stéphane Doly; Sophie M. Banas; Pothitos M. Pityc...; Imane Moutkine; Aude Muzerelle; Anna Tchenio; Anne Roumier; Manuel Mameli; Luc Maroteaux
• Keywords: Male; 0301 basic medicine; Serotonin; MDMA; Indoles; [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; Neurogenesis; 610; Action Potentials; Mice, Transgenic; Body Temperature; Mice; 03 medical and health sciences; https://purl.org/becyt/ford/1.6; Fluoxetine; 616; https://purl.org/becyt/ford/3.1; Receptor, Serotonin, 5-HT2B; SSRI; Animals; https://purl.org/becyt/ford/3; https://purl.org/becyt/ford/1; 3,4-Methylenedioxyamphetamine; Mice, Knockout; 8-Hydroxy-2-(di-n-propylamino)tetralin; Central Nervous System Sensitization; Prepulse Inhibition; Amphetamines; [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology; Conditional knock-out; Molecular Biology/Molecular biology; 3. Good health; Electrophysiology; [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics; Viral overexpression; [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry; [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health; [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology; Raphe Nuclei; Female; Serotonin 5-HT2 Receptor Agonists; Serotonergic Neurons

Serotonin is a neurotransmitter involved in many psychiatric diseases. In humans, a lack of 5-HT2B receptors is associated with serotonin-dependent phenotypes, including impulsivity and suicidality. A lack of 5-HT2B receptors in mice eliminates the effects of molecules that directly target serotonergic neurons including amphetamine derivative serotonin releasers, and selective serotonin reuptake inhibitor antidepressants. In this work, we tested the hypothesis that 5-HT2B receptors directly and positively regulate raphe serotonin neuron activity. By ex vivo electrophysiological recordings, we report that stimulation by the 5-HT2B receptor agonist, BW723C86, increased the firing frequency of serotonin Pet1-positive neurons. Viral overexpression of 5-HT2B receptors in these neurons increased their excitability. Furthermore, in vivo 5-HT2B-receptor stimulation by BW723C86 counteracted 5-HT1A autoreceptor-dependent reduction in firing rate and hypothermic response in wild-type mice. By a conditional genetic ablation that eliminates 5-HT2B receptor expression specifically and exclusively from Pet1-positive serotonin neurons (Htr2b 5-HTKO mice), we demonstrated that behavioral and sensitizing effects of MDMA (3,4-methylenedioxy-methamphetamine), as well as acute behavioral and chronic neurogenic effects of the antidepressant fluoxetine, require 5-HT2B receptor expression in serotonergic neurons. In Htr2b 5-HTKO mice, dorsal raphe serotonin neurons displayed a lower firing frequency compared to control Htr2b lox/lox mice as assessed by in vivo extracellular recordings and a stronger hypothermic effect of 5-HT1A-autoreceptor stimulation was observed. The increase in head-twitch response to DOI (2,5-dimethoxy-4-iodoamphetamine) further confirmed the lower serotonergic tone resulting from the absence of 5-HT2B receptors in serotonin neurons. Together, these observations indicate that the 5-HT2B receptor acts as a direct positive modulator of serotonin Pet1-positive neurons in an opposite way as the known 5-HT1A-negative autoreceptor.