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Somato-Dendritic Regulation of Raphe Serotonin Neurons; A Key to Antidepressant Action.

ABSTRACT: Several lines of evidence implicate serotonin (5-hydroxytryptamine, 5-HT)in regulating personality traits and mood control. Serotonergic neurons are classically thought to be tonic regular-firing, "clock-like" neurons. Neurotransmission by serotonin is tightly regulated by the serotonin transporter (SERT) and by autoreceptors (serotonin receptors expressed by serotonin neurons) through negative feedback inhibition at the cell bodies and dendrites (5-HT1A receptors) of the dorsal raphe nuclei or at the axon terminals (5-HT1B receptors). In dorsal raphe neurons, the release of serotonin from vesicles in the soma, dendrites, and/or axonal varicosities is independent of classical synapses and can be induced by neuron depolarization, by the stimulation of L-type calcium channels, by activation of glutamatergic receptors, and/or by activation of 5-HT2 receptors. The resulting serotonin release displays a slow kinetic and a large diffusion. This process called volume transmission may ultimately affect the rate of discharge of serotonergic neurons, and their tonic activity. The therapeutic effects induced by serotonin-selective reuptake inhibitor (SSRI) antidepressants are initially triggered by blocking SERT but rely on consequences of chronic exposure, i.e., a selective desensitization of somatodendritic 5-HT1A autoreceptors. Agonist stimulation of 5-HT2B receptors mimicked behavioral and neurogenic SSRI actions, and increased extracellular serotonin in dorsal raphe. By contrast, a lack of effects of SSRIs was observed in the absence of 5-HT2B receptors (knockout-KO), even restricted to serotonergic neurons (Htr2b5-HTKO mice). The absence of 5-HT2B receptors in serotonergic neurons is associated with a higher 5-HT1A-autoreceptor reactivity and thus a lower firing activity of these neurons. In agreement, mice with overexpression of 5-HT1A autoreceptor show decreased neuronal activity and increased depression-like behavior that is resistant to SSRI treatment. We propose thus that the serotonergic tone results from the opposite control exerted by somatodendritic (Gi-coupled) 5-HT1A and (Gq-coupled) 5-HT2B receptors on dorsal raphe neurons. Therefore, 5-HT2B receptors may contribute to SSRI therapeutic effects by their positive regulation of adult raphe serotonergic neurons. Deciphering the molecular mechanism controlling extrasynaptic release of serotonin, and how autoreceptors interact in regulating the tonic activity of serotonergic neurons, is critical to fully understand the therapeutic effect of SSRIs.

SUBMITTER: Quentin E

PROVIDER: S-EPMC6307465 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Somato-Dendritic Regulation of Raphe Serotonin Neurons; A Key to Antidepressant Action.

Quentin Emily E Belmer Arnauld A Maroteaux Luc L

Frontiers in neuroscience 20181220

Several lines of evidence implicate serotonin (5-hydroxytryptamine, 5-HT)in regulating personality traits and mood control. Serotonergic neurons are classically thought to be tonic regular-firing, "clock-like" neurons. Neurotransmission by serotonin is tightly regulated by the serotonin transporter (SERT) and by autoreceptors (serotonin receptors expressed by serotonin neurons) through negative feedback inhibition at the cell bodies and dendrites (5-HT<sub>1A</sub> receptors) of the dorsal raphe ...[more]

PMID: 30618598

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Project description: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.

Dataset Information

Somato-Dendritic Regulation of Raphe Serotonin Neurons; A Key to Antidepressant Action.

Publications

Somato-Dendritic Regulation of Raphe Serotonin Neurons; A Key to Antidepressant Action.

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