Publications by authors named "Luc Maroteaux"

63 Publications

Serotonin 2B Receptor by Interacting with NMDA Receptor and CIPP Protein Complex May Control Structural Plasticity at Glutamatergic Synapses.

ACS Chem Neurosci 2021 04 19;12(7):1133-1149. Epub 2021 Mar 19.

INSERM UMR-S 1270, F75005 Paris, France.

The serotonin 2B (5-HT) receptor coupled to Gq-protein contributes to the control of neuronal excitability and is implicated in various psychiatric disorders. The mechanisms underlying its brain function are not fully described. Using peptide affinity chromatography combined with mass spectrometry, we found that the PDZ binding motif of the 5-HT receptor located at its C-terminal end interacts with the scaffolding protein channel interacting PDZ protein (CIPP). We then showed, in COS-7 cells, that the association of the 5-HT receptor to CIPP enhanced receptor-operated inositol phosphate (IP) production without affecting its cell surface and intracellular levels. Co-immunoprecipitation experiments revealed that CIPP, the 5-HT receptor, and the NR1 subunit of the NMDA receptor form a macromolecular complex. CIPP increased 5-HT receptor clustering at the surface of primary cultured hippocampal neurons and prevented receptor dispersion following agonist stimulation, thus potentiating IP production and intracellular calcium mobilization in dendrites. CIPP or 5-HT receptor stimulation in turn dispersed NR1 clusters colocalized with 5-HT receptors and increased the density and maturation of dendritic spines. Collectively, our results suggest that the 5-HT receptor, the NMDA receptor, and CIPP may form a signaling platform by which serotonin can influence structural plasticity of excitatory glutamatergic synapses.
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http://dx.doi.org/10.1021/acschemneuro.0c00638DOI Listing
April 2021

Targeting 5-HT Receptor Signaling Prevents Border Zone Expansion and Improves Microstructural Remodeling After Myocardial Infarction.

Circulation 2021 Mar 21;143(13):1317-1330. Epub 2021 Jan 21.

Department of Biomedical Engineering, Vanderbilt University, Nashville, TN (J.C.S., L.A.R., N.T.M., M.R.B., R.G., A.M.-J., W.D.M.).

Background: Myocardial infarction (MI) induces an intense injury response that ultimately generates a collagen-dominated scar. Although required to prevent ventricular rupture, the fibrotic process is often sustained in a manner detrimental to optimal recovery. Cardiac myofibroblasts are the cells tasked with depositing and remodeling collagen and are a prime target to limit the fibrotic process after MI. Serotonin 2B receptor (5-HT) signaling has been shown to be harmful in a variety of cardiopulmonary pathologies and could play an important role in mediating scar formation after MI.

Methods: We used 2 pharmacological antagonists to explore the effect of 5-HT inhibition on outcomes after MI and characterized the histological and microstructural changes involved in tissue remodeling. Inducible 5-HT ablation driven by and was used to evaluate resident cardiac fibroblast- and myofibroblast-specific contributions of 5-HT, respectively. RNA sequencing was used to motivate subsequent in vitro analyses to explore cardiac fibroblast phenotype.

Results: 5-HT antagonism preserved cardiac structure and function by facilitating a less fibrotic scar, indicated by decreased scar thickness and decreased border zone area. 5-HT antagonism resulted in collagen fiber redistribution to thinner collagen fibers that were more anisotropic, enhancing left ventricular contractility, whereas fibrotic tissue stiffness was decreased, limiting the hypertrophic response of uninjured cardiomyocytes. Using a tamoxifen-inducible Cre, we ablated 5-HT from -lineage resident cardiac fibroblasts and saw similar improvements to the pharmacological approach. Tamoxifen-inducible Cre-mediated ablation of 5-HT after onset of injury in -lineage myofibroblasts also improved cardiac outcomes. RNA sequencing and subsequent in vitro analyses corroborate a decrease in fibroblast proliferation, migration, and remodeling capabilities through alterations in expression and Src phosphorylation.

Conclusions: Together, our findings illustrate that 5-HT expression in either cardiac fibroblasts or activated myofibroblasts directly contributes to excessive scar formation, resulting in adverse remodeling and impaired cardiac function after MI.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009826PMC
March 2021

International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function.

Pharmacol Rev 2021 01;73(1):310-520

Neuropharmacology Research Group, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (N.M.B., A.R.); Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia (N.M.B., D.H.); Department of Pharmacology, Georgetown University Medical Center, Washington, DC (G.P.A.); Institut de Génomique Functionnelle, Université Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France (C.B., J.B., S.C.-D., S.C., P.M.); Université de Montpellier, Montpellier, France (C.B., J.B., S.C.-D., S.C., P.M.); C.E.N.T.E.R. Division of Gastroenterology and Hepatology Mayo Clinic, Rochester, Minnesota (M.C.); Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (K.A.C., R.M.H.); School of Life Sciences, Medical School, Queen's Medical Centre, The University of Nottingham, Nottingham, United Kingdom (K.C.F.); Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York (M.G.); Laboratory of Neurophysiology, Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta (G.D.G.); Department of Physiology, Department of Obstetrics and Gynaecology, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada (N.M.G., E.K.L.); Department of Psychiatry, University of California San Diego, La Jolla, California (A.L.H.); Theranyx, Marseille, France (G.H.); Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, New York (K.H.-D.); Ecole Polytechnique Fédérale de Lausanne, Institute of Chemical Sciences and Engineering, Lausanne, Switzerland (R.H., H.V.); Department of Pharmacy-Drug Science, University of Bari Aldo Moro, Bari, Italy (E.L., M.L.); Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway (F.O.L.); Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (S.C.R.L.); INSERM UMR-S 1270, Paris, France (L.M., A.R.); Sorbonne Université, Paris, France (L.M., A.R.); Institut du Fer à Moulin, Paris, France (L.M., A.R.); Drug Development, Grunenthal GmbH, Aachen, Germany (A.C.M.); Tucson, Arizona (D.L.N.); Departments of Psychiatry and Behavioral Sciences and Pharmacology, University of Washington, Seattle, Washington (J.F.N.); Neurolixis Inc., Dana Point, California (A.N.-T.); Université Grenoble Alpes, Institut de Biologie Structurale, Grenoble, France (H.N.); CNRS, Institut de Biologie Structurale, Grenoble, France (H.N.); Commissariat à l'Energie Atomique et aux Energies Alternatives, DSV, Institut de Biologie Structurale, Grenoble, France (H.N.); Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina (B.L.R.); Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom (G.J.S.); Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York (M.T.); Department of Pharmacology, University of Oxford, Oxford, United Kingdom (T.S.); Cinvestav-Coapa, Pharmacobiology, Mexico City, Tlalpan, Mexico (C.M.V.); Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (S.W.W.); The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia (D.H.); and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California (D.H.).

5-HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role 5-HT receptors play in physiologic and pathophysiological processes. The present review offers a framework for the official receptor nomenclature and a detailed understanding of each of the 14 5-HT receptor subtypes, their roles in the systems of the body, and, where appropriate, the (potential) utility of therapeutics targeting these receptors. SIGNIFICANCE STATEMENT: This review provides a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit.
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http://dx.doi.org/10.1124/pr.118.015552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770494PMC
January 2021

The serotonin 2B receptor is required in neonatal microglia to limit neuroinflammation and sickness behavior in adulthood.

Glia 2021 03 23;69(3):638-654. Epub 2020 Oct 23.

INSERM UMR-S 1270, Paris, France.

Severe peripheral infections induce an adaptive sickness behavior and an innate immune reaction in various organs including the brain. On the long term, persistent alteration of microglia, the brain innate immune cells, is associated with an increased risk of psychiatric disorders. It is thus critical to identify genes and mechanisms controlling the intensity and duration of the neuroinflammation induced by peripheral immune challenges. We tested the hypothesis that the 5-HT receptor, the main serotonin receptor expressed by microglia, might represent a valuable candidate. First, we observed that Htr2b mice, knock-out for the 5-HT receptor gene, developed, when exposed to a peripheral lipopolysaccharide (LPS) challenge, a stronger weight loss compared to wild-type mice; in addition, comparison of inflammatory markers in brain, 4 and 24 hr after LPS injection, showed that Htr2b deficiency leads to a prolonged neuroinflammation. Second, to assess the specific contribution of the microglial 5-HT receptor, we investigated the response to LPS of conditional knock-out mice invalidated for Htr2b in microglia only. We found that deletion of Htr2b in microglia since birth is sufficient to cause enhanced weight loss and increased neuroinflammatory response upon LPS injection at adult stage. In contrast, mice deleted for microglial Htr2b in adulthood responded normally to LPS, revealing a neonatal developmental effect. These results highlight the role of microglia in the response to a peripheral immune challenge and suggest the existence of a developmental, neonatal period, during which instruction of microglia through 5-HT receptors is necessary to prevent microglia overreactivity in adulthood.
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http://dx.doi.org/10.1002/glia.23918DOI Listing
March 2021

Serotonin (5-HT) Shapes the Macrophage Gene Profile through the 5-HT-Dependent Activation of the Aryl Hydrocarbon Receptor.

J Immunol 2020 05 6;204(10):2808-2817. Epub 2020 Apr 6.

Laboratorio de Células Mieloides, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain;

Macrophages can either promote or resolve inflammatory responses, and their polarization state is modulated by peripheral serotonin (5-hydroxytryptamine [5-HT]). In fact, pro- and anti-inflammatory macrophages differ in the expression of serotonin receptors, with 5-HT and 5-HT expression restricted to M-CSF-primed monocyte-derived macrophages (M-MØ). 5-HT drives the acquisition of profibrotic and anti-inflammatory functions in M-MØ, whereas 5-HT prevents the degeneration of spinal cord mononuclear phagocytes and modulates motility of murine microglial processes. Because 5-HT mediates clinically relevant 5-HT-related pathologies (valvular heart disease, pulmonary arterial hypertension) and is an off target of anesthetics, antiparkinsonian drugs, and selective serotonin reuptake inhibitors, we sought to determine the transcriptional consequences of 5-HT engagement in human macrophages, for which 5-HT signaling remains unknown. Assessment of the effects of specific agonists and antagonist revealed that 5-HT engagement modifies the cytokine and gene signature of anti-inflammatory M-MØ, upregulates the expression of aryl hydrocarbon receptor (AhR) target genes, and stimulates the transcriptional activation of AhR. Moreover, we found that 5-HT dose dependently upregulates the expression of AhR target genes in M-MØ and that the 5-HT-mediated activation of AhR is 5-HT dependent because it is abrogated by the 5-HT-specific antagonist SB204741. Altogether, our results demonstrate the existence of a functional 5-HT/5-HT/AhR axis in human macrophages and indicate that 5-HT potentiates the activity of a transcription factor (AhR) that regulates immune responses and the biological responses to xenobiotics.
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http://dx.doi.org/10.4049/jimmunol.1901531DOI Listing
May 2020

Morphine withdrawal recruits lateral habenula cytokine signaling to reduce synaptic excitation and sociability.

Nat Neurosci 2019 07 17;22(7):1053-1056. Epub 2019 Jun 17.

The Department of Fundamental Neuroscience, The University of Lausanne, Lausanne, Switzerland.

The lateral habenula encodes aversive stimuli contributing to negative emotional states during drug withdrawal. Here we report that morphine withdrawal in mice leads to microglia adaptations and diminishes glutamatergic transmission onto raphe-projecting lateral habenula neurons. Chemogenetic inhibition of this circuit promotes morphine withdrawal-like social deficits. Morphine withdrawal-driven synaptic plasticity and reduced sociability require tumor necrosis factor-α (TNF-α) release and neuronal TNF receptor 1 activation. Hence, habenular cytokines control synaptic and behavioral adaptations during drug withdrawal.
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http://dx.doi.org/10.1038/s41593-019-0421-4DOI Listing
July 2019

Enhanced Renewal of Erythroid Progenitors in Myelodysplastic Anemia by Peripheral Serotonin.

Cell Rep 2019 03;26(12):3246-3256.e4

Institut Imagine, INSERM U1163, CNRS ERL 8254, Université Paris Descartes, Sorbonne Paris-Cité, Laboratoire d'Excellence GR-Ex, Paris, France. Electronic address:

Tryptophan as the precursor of several active compounds, including kynurenine and serotonin, is critical for numerous important metabolic functions. Enhanced tryptophan metabolism toward the kynurenine pathway has been associated with myelodysplastic syndromes (MDSs), which are preleukemic clonal diseases characterized by dysplastic bone marrow and cytopenias. Here, we reveal a fundamental role for tryptophan metabolized along the serotonin pathway in normal erythropoiesis and in the physiopathology of MDS-related anemia. We identify, both in human and murine erythroid progenitors, a functional cell-autonomous serotonergic network with pro-survival and proliferative functions. In vivo studies demonstrate that pharmacological increase of serotonin levels using fluoxetine, a common antidepressant, has the potential to become an important therapeutic strategy in low-risk MDS anemia refractory to erythropoietin.
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http://dx.doi.org/10.1016/j.celrep.2019.02.071DOI Listing
March 2019

Two-photon Imaging of Microglial Processes' Attraction Toward ATP or Serotonin in Acute Brain Slices.

J Vis Exp 2019 01 31(143). Epub 2019 Jan 31.

Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 1270 Paris, France; Sorbonne Université, Paris, France; Institut du Fer à Moulin, Paris, France;

Microglial cells are resident innate immune cells of the brain that constantly scan their environment with their long processes and, upon disruption of homeostasis, undergo rapid morphological changes. For example, a laser lesion induces in a few minutes an oriented growth of microglial processes, also called "directional motility", toward the site of injury. A similar effect can be obtained by delivering locally ATP or serotonin (5-hydroxytryptamine [5-HT]). In this article, we describe a protocol to induce a directional growth of microglial processes toward a local application of ATP or 5-HT in acute brain slices of young and adult mice and to image this attraction over time by multiphoton microscopy. A simple method of quantification with free and open-source image analysis software is proposed. A challenge that still characterizes acute brain slices is the limited time, decreasing with age, during which the cells remain in a physiological state. This protocol, thus, highlights some technical improvements (medium, air-liquid interface chamber, imaging chamber with a double perfusion) aimed at optimizing the viability of microglial cells over several hours, especially in slices from adult mice.
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http://dx.doi.org/10.3791/58788DOI Listing
January 2019

Dimers of serotonin receptors: Impact on ligand affinity and signaling.

Biochimie 2019 Jun 24;161:23-33. Epub 2019 Jan 24.

INSERM UMR-S839, S1270, Paris, 75005, France; Sorbonne Université, Paris, 75005, France; Institut du Fer à Moulin, Paris, 75005, France.

Membrane receptors often form complexes with other membrane proteins that directly interact with different effectors of the signal transduction machinery. G-protein-coupled receptors (GPCRs) were for long time considered as single pharmacological entities. However, evidence for oligomerization appeared for various classes and subtypes of GPCRs. This review focuses on metabotropic serotonin (5-hydroxytryptamine, 5-HT) receptors, which belong to the rhodopsin-like class A of GPCRs, and will summarize the convergent evidence that homo- and hetero-dimers containing 5-HT receptors exist in transfected cells and in-vivo. We will show that complexes involving 5-HT receptors may acquire new signal transduction pathways and new physiological roles. In some cases, these complexes participate in disease-specific deregulations, that can be differentially affected by various drugs. Hence, selecting receptor complex-specific responses of these heterodimers may constitute an emerging strategy likely to improve beneficial therapeutic effects.
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http://dx.doi.org/10.1016/j.biochi.2019.01.009DOI Listing
June 2019

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

Front Neurosci 2018 20;12:982. Epub 2018 Dec 20.

INSERM UMR-S 839, Institut du Fer à Moulin, Paris, France.

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 receptors) of the dorsal raphe nuclei or at the axon terminals (5-HT 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-HT 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-HT autoreceptors. Agonist stimulation of 5-HT 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-HT receptors (knockout-KO), even restricted to serotonergic neurons ( mice). The absence of 5-HT receptors in serotonergic neurons is associated with a higher 5-HT-autoreceptor reactivity and thus a lower firing activity of these neurons. In agreement, mice with overexpression of 5-HT 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-HT and (Gq-coupled) 5-HT receptors on dorsal raphe neurons. Therefore, 5-HT 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.
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http://dx.doi.org/10.3389/fnins.2018.00982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307465PMC
December 2018

A positive association between a polymorphism in the gene and cocaine-crack in a French Afro-Caribbean population.

World J Biol Psychiatry 2020 12 28;21(10):784-789. Epub 2019 Jan 28.

Department of Psychiatry and Addictive Disorders, University Sorbonne Paris-Cité (Faculty of Medicine Paris Descartes), INSERM UMR 894-Team1 Center of Psychiatry and Neuroscience, University Hospital Cochin (site Tarnier), Paris, France.

Objectives: Cocaine dependence has a strong heritability component. The aim of this study was to investigate the putative association between the serotonin 2B receptor gene (), crack use disorders and impulsivity.

Methods: A French Afro-Caribbean male population of patients with crack use disorders ( = 80) was compared to healthy Afro-Caribbean male controls ( = 60). Comorbid ADHD and impulsivity were assessed. Five single nucleotide polymorphisms (SNPs) in the gene were selected: rs643700, rs6736017, rs1549339, rs17586428 and rs3806545. These SNPs were chosen to include most of the linkage disequilibrium blocks in the gene. The French translation of the Barratt Impulsivity Scale BIS-11 was used to evaluate impulsivity. Comorbid ADHD was diagnosed using the Wender Utah Rating Scale-25 item for Attention Deficit-Hyperactivity Disorder.

Results: We have observed a positive association between the rs6736017 polymorphism and crack use disorders in a French Afro-Caribbean male population.

Conclusions: In our population, the risk effect of rs6736017 appeared to be specific to individuals with crack use disorders rather than being driven by impulsivity or ADHD alone.
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http://dx.doi.org/10.1080/15622975.2018.1563721DOI Listing
December 2020

Frontiers of Serotonin Beyond the Brain.

Pharmacol Res 2019 02 22;140:1-6. Epub 2018 Oct 22.

Departments of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address:

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http://dx.doi.org/10.1016/j.phrs.2018.10.022DOI Listing
February 2019

Regulation of raphe serotonin neurons by serotonin 1A and 2B receptors.

Neuropsychopharmacology 2019 01;44(1):218-219

INSERM U 839, Paris, 75005, France.

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http://dx.doi.org/10.1038/s41386-018-0214-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235922PMC
January 2019

Evolutionary considerations on 5-HT receptors.

Pharmacol Res 2019 02 14;140:14-20. Epub 2018 Sep 14.

INSERM UMR-S839, Paris, 75005, France; Sorbonne Université, Paris, 75005, France; Institut du Fer à Moulin, Paris, 75005, France. Electronic address:

Serotonin is a neurotransmitter widely conserved from ancient organisms lacking nervous systems through man, and its presence precedes the appearance of nervous systems on both developmental and evolutionary time scales. Serotonin receptor subtypes diversified approximately at the time period during which vertebrates diverged from invertebrates. The biological and clinical importance of serotonin receptors, may benefit from studies on their evolution. Although potentially informative about their pathophysiological functions, reviews on this topic are sparse. Several observations support basic functions mediated by serotonin, both in periphery and central nervous system. In particular, 5-HT receptors have been implicated in embryonic development, including cell proliferation, survival, and/or differentiation, in either neural crest cell derivatives, myeloid cell lineage, or heart embryogenesis. In this review, we collected existing data about the genomic association between the RPN2 proteasome subunit gene Psmd1 and the 5-HT receptor gene Htr2b. We discuss about the possibility that, during genome duplications, a single copy of this pair of genes has been conserved, suggesting a strong selective pressure. Many basic physiological functions in which serotonin system is involved could be linked to the early association of these two genes in pre-vertebrates. Their evolutionary association highlights the possibility that the 5-HT receptor gene, Htr2b, is the common ancestor of 5-HT-receptor subfamily. Disentangling these possibilities could bring new understanding of the respective importance of these receptors in pathophysiology of serotonin.
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http://dx.doi.org/10.1016/j.phrs.2018.09.014DOI Listing
February 2019

Adiporon, an adiponectin receptor agonist acts as an antidepressant and metabolic regulator in a mouse model of depression.

Transl Psychiatry 2018 08 16;8(1):159. Epub 2018 Aug 16.

Université Côte d'Azur, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS, 660 Route des lucioles, Sophia Antipolis, 06560, Valbonne, France.

Major depression is a psychiatric disorder with complex etiology. About 30% of depressive patients are resistant to antidepressants that are currently available, likely because they only target the monoaminergic systems. Thus, identification of novel antidepressants with a larger action spectrum is urgently required. Epidemiological data indicate high comorbidity between metabolic and psychiatric disorders, particularly obesity and depression. We used a well-characterized anxiety/depressive-like mouse model consisting of continuous input of corticosterone for seven consecutive weeks. A panel of reliable behavioral tests were conducted to assessing numerous facets of the depression-like state, including anxiety, resignation, reduced motivation, loss of pleasure, and social withdrawal. Furthermore, metabolic features including weight, adiposity, and plasma biological parameters (lipids, adipokines, and cytokines) were investigated in corticosterone-treated mice. Our data show that chronic administration of corticosterone induced the parallel onset of metabolic and behavioral dysfunctions in mice. AdipoRon, a potent adiponectin receptor agonist, prevented the corticosterone-induced early onset of moderate obesity and metabolic syndromes. Moreover, in all the behavioral tests, daily treatment with AdipoRon successfully reversed the corticosterone-induced depression-like state in mice. AdipoRon exerted its pleiotropic actions on various systems including hippocampal neurogenesis, serotonergic neurotransmission, neuroinflammation, and the tryptophan metabolic pathway, which can explain its antidepressant properties. Our study highlights the pivotal role of the adiponergic system in the development of both metabolic and psychiatric disorders. AdipoRon may constitute a promising novel antidepressant.
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http://dx.doi.org/10.1038/s41398-018-0210-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095913PMC
August 2018

Translational studies support a role for serotonin 2B receptor (HTR2B) gene in aggression-related cannabis response.

Mol Psychiatry 2018 12 6;23(12):2277-2286. Epub 2018 Jun 6.

Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.

Cannabis use is increasing in the United States, as are its adverse effects. We investigated the genetics of an adverse consequence of cannabis use: cannabis-related aggression (CRA) using a genome-wide association study (GWAS) design. Our GWAS sample included 3269 African Americans (AAs) and 2546 European Americans (EAs). An additional 89 AA subjects from the Grady Trauma Project (GTP) were also examined using a proxy-phenotype replication approach. We identified genome-wide significant risk loci contributing to CRA in AAs at the serotonin receptor 2B receptor gene (HTR2B), and the lead SNP, HTR2B*rs17440378, showed nominal association to aggression in the GTP cohort of cannabis-exposed subjects. A priori evidence linked HTR2B to impulsivity/aggression but not to cannabis response. Human functional data regarding the HTR2B variant further supported our finding. Treating an Htr2b knockout mouse with THC resulted in increased aggressive behavior, whereas wild-type mice following THC administration showed decreased aggression in the resident-intruder paradigm, demonstrating that HTR2B variation moderates the effects of cannabis on aggression. These concordant findings in mice and humans implicate HTR2B as a major locus associated with cannabis-induced aggression.
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http://dx.doi.org/10.1038/s41380-018-0077-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281782PMC
December 2018

Translational studies support a role for serotonin 2B receptor (HTR2B) gene in aggression-related cannabis response.

Mol Psychiatry 2018 12 6;23(12):2277-2286. Epub 2018 Jun 6.

Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.

Cannabis use is increasing in the United States, as are its adverse effects. We investigated the genetics of an adverse consequence of cannabis use: cannabis-related aggression (CRA) using a genome-wide association study (GWAS) design. Our GWAS sample included 3269 African Americans (AAs) and 2546 European Americans (EAs). An additional 89 AA subjects from the Grady Trauma Project (GTP) were also examined using a proxy-phenotype replication approach. We identified genome-wide significant risk loci contributing to CRA in AAs at the serotonin receptor 2B receptor gene (HTR2B), and the lead SNP, HTR2B*rs17440378, showed nominal association to aggression in the GTP cohort of cannabis-exposed subjects. A priori evidence linked HTR2B to impulsivity/aggression but not to cannabis response. Human functional data regarding the HTR2B variant further supported our finding. Treating an Htr2b knockout mouse with THC resulted in increased aggressive behavior, whereas wild-type mice following THC administration showed decreased aggression in the resident-intruder paradigm, demonstrating that HTR2B variation moderates the effects of cannabis on aggression. These concordant findings in mice and humans implicate HTR2B as a major locus associated with cannabis-induced aggression.
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http://dx.doi.org/10.1038/s41380-018-0077-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281782PMC
December 2018

Adaptive Control of Dorsal Raphe by 5-HT4 in the Prefrontal Cortex Prevents Persistent Hypophagia following Stress.

Cell Rep 2017 Oct;21(4):901-909

Department of Sciences, Brain, Anorexia & Addiction, Nîmes University, Nîmes 30000, France. Electronic address:

Transient reduced food intake (hypophagia) following high stress could have beneficial effects on longevity, but paradoxically, hypophagia can persist and become anorexia-like behavior. The neural underpinnings of stress-induced hypophagia and the mechanisms by which the brain prevents the transition from transient to persistent hypophagia remain undetermined. In this study, we report the involvement of a network governing goal-directed behavior (decision). This network consists of the ascending serotonergic inputs from the dorsal raphe nucleus (DR) to the medial prefrontal cortex (mPFC). Specifically, adult restoration of serotonin 4 receptor (5-HTR) expression in the mPFC rescues hypophagia and specific molecular changes related to depression resistance in the DR (5-HT release elevation, 5-HT receptor, and 5-HT transporter reductions) of stressed 5-HTR knockout mice. The adult mPFC-5-HTR knockdown mimics the null phenotypes. When mPFC-5-HTRs are overexpressed and DR-5-HT1ARs are blocked in the DR, hypophagia following stress persists, suggesting an antidepressant action of early anorexia.
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http://dx.doi.org/10.1016/j.celrep.2017.10.003DOI Listing
October 2017

Serotonin 2B Receptors in Mesoaccumbens Dopamine Pathway Regulate Cocaine Responses.

J Neurosci 2017 10 21;37(43):10372-10388. Epub 2017 Sep 21.

Institut national de la santé et de la recherche médicale, Unité Mixte de Recherche-S839, F-75005 Paris, France,

Addiction is a maladaptive pattern of behavior following repeated use of reinforcing drugs in predisposed individuals, leading to lifelong changes. Common among these changes are alterations of neurons releasing dopamine in the ventral and dorsal territories of the striatum. The serotonin 5-HT receptor has been involved in various behaviors, including impulsivity, response to antidepressants, and response to psychostimulants, pointing toward putative interactions with the dopamine system. Despite these findings, it remains unknown whether 5-HT receptors directly modulate dopaminergic activity and the possible mechanisms involved. To answer these questions, we investigated the contribution of 5-HT receptors to cocaine-dependent behavioral responses. Male mice permanently lacking 5-HT receptors, even restricted to dopamine neurons, developed heightened cocaine-induced locomotor responses. Retrograde tracing combined with single-cell mRNA amplification indicated that 5-HT receptors are expressed by mesolimbic dopamine neurons. and electrophysiological recordings showed that 5-HT-receptor inactivation in dopamine neurons affects their neuronal activity and increases AMPA-mediated over NMDA-mediated excitatory synaptic currents. These changes are associated with lower ventral striatum dopamine activity and blunted cocaine self-administration. These data identify the 5-HT receptor as a pharmacological intermediate and provide mechanistic insight into attenuated dopamine tone following exposure to drugs of abuse. Here we report that mice lacking 5-HT receptors totally or exclusively in dopamine neurons exhibit heightened cocaine-induced locomotor responses. Despite the sensitized state of these mice, we found that associated changes include lower ventral striatum dopamine activity and lower cocaine operant self-administration. We described the selective expression of 5-HT receptors in a subpopulation of dopamine neurons sending axons to the ventral striatum. Increased bursting properties of these dopamine neurons and a concomitant increase in AMPA synaptic transmission to dopamine neurons were found in mice lacking 5-HT receptors. These data support the idea that the chronic 5-HT-receptor inhibition makes mice behave like animals already exposed to cocaine with higher cocaine-induced locomotion associated with changes in dopamine neuron reactivity.
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http://dx.doi.org/10.1523/JNEUROSCI.1354-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596631PMC
October 2017

The role of 5-HT receptors in mitral valvulopathy: bone marrow mobilization of endothelial progenitors.

Br J Pharmacol 2017 Nov 15;174(22):4123-4139. Epub 2017 Oct 15.

Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire (EA7296), Faculté de Médecine, Fédération de Médecine Translationnelle, Université et Centre Hospitalier de Strasbourg, Strasbourg, France.

Background And Purpose: Valvular heart disease (VHD) is highly prevalent in industrialized countries. Chronic use of anorexigens, amphetamine or ergot derivatives targeting the 5-HT system is associated with VHD. Here, we investigated the contribution of 5-HT receptors in a model of valve degeneration induced by nordexfenfluramine, the main metabolite of the anorexigens, dexfenfluramine and benfluorex.

Experimental Approach: Nordexfenfluramine was infused chronically (28 days) in mice ((WT and transgenic Htr   , Htr   , and Htr   ) to induce mitral valve lesions. Bone marrow transplantation was also carried out. Haemodynamics were measured with echocardiography; tissues and cells were analysed by histology, immunocytochemistry, flow cytometry and RT -qPCR. Samples of human prolapsed mitral valves were also analysed.

Key Results: Chronic treatment of mice with nordexfenfluramine activated 5-HT receptors and increased valve thickness and cell density in a thick extracellular matrix, mimicking early steps of mitral valve remodelling. Lesions were prevented by 5-HT or 5-HT receptor antagonists and in transgenic Htr   or Htr   mice. Surprisingly, valve lesions were mainly formed by numerous non-proliferative CD34 endothelial progenitors. These progenitors originated from bone marrow (BM) as revealed by BM transplantation. The initial steps of mitral valve remodelling involved mobilization of BM-derived CD34 CD31 cells by 5-HT receptor stimulation. Analysis of human prolapsed mitral valves showing spontaneous degenerative lesions, demonstrated the presence of non-proliferating CD34 /CD309 /NOS3 endothelial progenitors expressing 5-HT receptors.

Conclusions And Implications: BM-derived endothelial progenitor cells make a crucial contribution to the remodelling of mitral valve tissue. Our data describe a new and important mechanism underlying human VHD.
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http://dx.doi.org/10.1111/bph.13981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680644PMC
November 2017

Heterodimers of serotonin receptor subtypes 2 are driven by 5-HT protomers.

J Biol Chem 2017 04 3;292(15):6352-6368. Epub 2017 Mar 3.

the Institut Cochin, INSERM U1016, CNRS UMR8104, Paris 75014,

The serotonin receptor subtypes 2 comprise 5-HT, 5-HT, and 5-HT, which are Gα-coupled receptors and display distinct pharmacological properties. Although co-expressed in some brain regions and involved in various neurological disorders, their functional interactions have not yet been studied. We report that 5-HT receptors can form homo- and heterodimers when expressed alone or co-expressed in transfected cells. Co-immunoprecipitation and bioluminescence resonance energy transfer studies confirmed that 5-HT receptors interact with either 5-HT or 5-HT receptors. Although heterodimerization with 5-HT receptors does not alter 5-HT Gα-dependent inositol phosphate signaling, 5-HT or 5-HT receptor-mediated signaling was totally blunted. This feature can be explained by a dominance of 5-HT on 5-HT and 5-HT receptor binding; in 5-HT-containing heterodimers, ligands bind and activate the 5-HT protomer exclusively. This dominant effect on the associated protomer was also observed in neurons, supporting the physiological relevance of 5-HT receptor heterodimerization Accordingly, exogenous expression of an inactive form of the 5-HT receptor in the locus ceruleus is associated with decreased 5-HT-dependent noradrenergic transmission. These data demonstrate that 5-HT receptors can form functionally asymmetric heterodimers and that must be considered when analyzing the physiological or pathophysiological roles of serotonin in tissues where 5-HT receptors are co-expressed.
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http://dx.doi.org/10.1074/jbc.M117.779041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391763PMC
April 2017

Serotonin transporter protects the placental cells against apoptosis in caspase 3-independent pathway.

J Cell Physiol 2017 Dec 12;232(12):3520-3529. Epub 2017 Apr 12.

Departments of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, Arkansas.

Serotonin (5-HT) and its specific transporter, SERT play important roles in pregnancy. Using placentas dissected from 18d gestational SERT-knock out (KO), peripheral 5-HT (TPH1)-KO, and wild-type (WT) mice, we explored the role of 5-HT and SERT in placental functions in detail. An abnormal thick band of fibrosis and necrosis under the giant cell layer in SERT-KO placentas appeared only moderately in TPH1-KO and minimally present in WT placentas. The majority of the changes were located at the junctional zone of the placentas in SERT. The etiology of these findings was tested with TUNEL assays. The placentas from SERT-KO and TPH1-KO showed 49- and 8-fold increase in TUNEL-positive cells without a concurrent change in the DNA repair or cell proliferation compared to WT placentas. While the proliferation rate in the embryos of TPH1-KO mice was 16-fold lower than the rate in gestational age matched embryos of WT or SERT-KO mice. These findings highlight an important role of continuous 5-HT signaling on trophoblast cell viability. SERT may contribute to protecting trophoblast cells against cell death via terminating the 5-HT signaling which changes cell death ratio in trophoblast as well as proliferation rate in embryos. However, the cell death in SERT-KO placentas is in caspase 3-independent pathway.
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http://dx.doi.org/10.1002/jcp.25812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522371PMC
December 2017

Cardiovascular remodeling and the peripheral serotonergic system.

Arch Cardiovasc Dis 2017 Jan 21;110(1):51-59. Epub 2016 Dec 21.

Laboratoire de neurobiologie et pharmacologie cardiovasculaire (EA7296), faculté de médecine, fédération de médecine translationnelle, laboratoire de neurobiologie et pharmacologie cardiovasculaire (EA7296), université et centre hospitalier de Strasbourg, 67085 Strasbourg, France. Electronic address:

Plasma 5-hydroxytryptamine (5-HT; serotonin), released from blood platelets, plays a major role in the human cardiovascular system. Besides the effect of endogenous serotonin, many drugs targeting serotonergic receptors are widely used in the general population (antiobesity agents, antidepressants, antipsychotics, antimigraine agents), and may enhance the cardiovascular risk. Depending on the type of serotonin receptor activated and its location, the use of these compounds triggers acute and chronic effects. The acute cardiovascular response to 5-HT, named the Bezold-Jarish reflex, leads to intense bradycardia associated with atrioventricular block, and involves 5-HT, 5-HT, 5-HT and 5-HT receptors. The chronic contribution of 5-HT and its receptors (5-HT and 5-HT) in cardiovascular tissue remodeling, with a particular emphasis on cardiac hypertrophy, fibrosis and valve degeneration, will be explored in this review. Finally, through the analysis of the effects of sarpogrelate, some new aspects of 5-HT receptor pharmacology in vasomotor tone regulation and the interaction between endothelial and smooth muscle cells will also be discussed. The aim of this review is to emphasize the cardiac side effects caused by serotonin receptor activation, and to highlight their possible prevention by the development of new drugs targeting this system.
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http://dx.doi.org/10.1016/j.acvd.2016.08.002DOI Listing
January 2017

New therapeutic opportunities for 5-HT receptor ligands.

Pharmacol Ther 2017 02 19;170:14-36. Epub 2016 Oct 19.

Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire EA7296, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg, Université et Centre Hospitalier de Strasbourg, Strasbourg, France. Electronic address:

Serotonergic dysfunction is mainly associated with neuropsychiatric and cardiovascular disorders but has also been linked with many other pathological conditions. Serotonin (5-hydroxytryptamine, 5-HT) mediates numerous physiological functions in the brain and the periphery by activating a variety of receptors. 5-HT receptors are divided into four classes, three of which belong to the G protein-coupled receptor family. This review provides an overview of the recent pharmacological developments involving the Gq-coupled 5-HT receptor subfamily as well as the pathological implications of this receptor subfamily with regard to fibrosis, the central nervous system, cardiovascular disorders, and cancer. The final section highlights new therapeutic opportunities and emerging research revealing unexplored medical opportunities for this class of 5-HT receptors. The development of biased 5-HT receptor ligands appears to be an interesting topic in various areas. In light of recent discoveries, the need for the development of new and safer drugs should take into account the risk of cardiovascular side effects such as pulmonary hypertension and heart valve disease.
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http://dx.doi.org/10.1016/j.pharmthera.2016.10.008DOI Listing
February 2017

[Pulmonary arterial hypertension, bone marrow, endothelial cell precursors and serotonin].

Biol Aujourdhui 2016 30;210(2):79-88. Epub 2016 Sep 30.

INSERM UMR-S 839, Université Pierre et Marie Curie, 75005 Paris, France - Institut du Fer à Moulin, 17 rue du Fer à Moulin, 75005 Paris, France.

Serotonin and bone-marrow-derived stem cells participate together in triggering pulmonary hypertension. Our work has shown that the absence of 5-HT2B receptors generates permanent changes in the composition of the blood and bone-marrow in the myeloid lineages, particularly in endothelial cell progenitors. The initial functions of 5-HT2B receptors in pulmonary arterial hypertension (PAH) are restricted to bone-marrow cells. They contribute to the differentiation/proliferation/mobilization of endothelial progenitor cells from the bone-marrow. Those bone-marrow-derived cells have a critical role in the development of pulmonary hypertension and pulmonary vascular remodeling. These data indicate that bone-marrow derived endothelial progenitors play a key role in the pathogenesis of PAH and suggest that interactions involving serotonin and bone morphogenic protein type 2 receptor (BMPR2) could take place at the level of the bone-marrow.
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http://dx.doi.org/10.1051/jbio/2016012DOI Listing
January 2017

Discrepancy in Insulin Regulation between Gestational Diabetes Mellitus (GDM) Platelets and Placenta.

J Biol Chem 2016 Apr 26;291(18):9657-65. Epub 2016 Feb 26.

From the Departments of Biochemistry and Molecular Biology, and

Earlier findings have identified the requirement of insulin signaling on maturation and the translocation of serotonin (5-HT) transporter, SERT to the plasma membrane of the trophoblast in placenta. Because of the defect on insulin receptor (IR) in the trophoblast of the gestational diabetes mellitus (GDM)-associated placenta, SERT is found entrapped in the cytoplasm of the GDM-trophoblast. SERT is encoded by the same gene expressed in trophoblast and platelets. Additionally, alteration in plasma 5-HT levels and the 5-HT uptake rates are associated with the aggregation rates of platelets. Therefore, here, we investigated a novel hypothesis that GDM-associated defects in platelet IR should change their 5-HT uptake rates, and this should be a leading factor for thrombosis in GDM maternal blood. The maternal blood and the placentas were obtained at the time of cesarean section from the GDM and non-diabetic subjects (n = 6 for each group), and the platelets and trophoblasts were isolated to determine the IR activity, surface level of SERT, and their 5-HT uptake rates.Interestingly, no significant differences were evident in IR tyrosine phosphorylation or the downstream elements, AKT and S6K in platelets and their aggregation rates in both groups. Furthermore, insulin stimulation up-regulated 5-HT uptake rates of GDM-platelets as it does in the control group. However, the phosphorylation of IR and the downstream elements were significantly lower in GDM-trophoblast and showed no response to the insulin stimulation while they showed 4-fold increase to insulin stimulation in control group. Similarly, the 5-HT uptake rates of GDM-trophoblast and the SERT expression on their surface were severalfold lower compared with control subjects. IR is expressed in all tissues, but it is not known if diabetes affects IR in all tissues equally. Here, for the first time, our findings with clinical samples show that in GDM-associated defect on IR is tissue type-dependent. While IR is impaired in GDM-placenta, it is unaffected in GDM-platelet.
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http://dx.doi.org/10.1074/jbc.M116.713693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850303PMC
April 2016

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis.

Acta Neuropathol 2016 Mar 7;131(3):465-80. Epub 2016 Jan 7.

INSERM UMR-S1118, Faculté de Médecine, bat 3, 8e etage, 11 rue Humann, 67085, Strasbourg Cedex, France.

Microglia are the resident mononuclear phagocytes of the central nervous system and have been implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). During neurodegeneration, microglial activation is accompanied by infiltration of circulating monocytes, leading to production of multiple inflammatory mediators in the spinal cord. Degenerative alterations in mononuclear phagocytes are commonly observed during neurodegenerative diseases, yet little is known concerning the mechanisms leading to their degeneration, or the consequences on disease progression. Here we observed that the serotonin 2B receptor (5-HT2B), a serotonin receptor expressed in microglia, is upregulated in the spinal cord of three different transgenic mouse models of ALS. In mutant SOD1 mice, this upregulation was restricted to cells positive for CD11b, a marker of mononuclear phagocytes. Ablation of 5-HT2B receptor in transgenic ALS mice expressing mutant SOD1 resulted in increased degeneration of mononuclear phagocytes, as evidenced by fragmentation of Iba1-positive cellular processes. This was accompanied by decreased expression of key neuroinflammatory genes but also loss of expression of homeostatic microglial genes. Importantly, the dramatic effect of 5-HT2B receptor ablation on mononuclear phagocytes was associated with acceleration of disease progression. To determine the translational relevance of these results, we studied polymorphisms in the human HTR2B gene, which encodes the 5-HT2B receptor, in a large cohort of ALS patients. In this cohort, the C allele of SNP rs10199752 in HTR2B was associated with longer survival. Moreover, patients carrying one copy of the C allele of SNP rs10199752 showed increased 5-HT2B mRNA in spinal cord and displayed less pronounced degeneration of Iba1 positive cells than patients carrying two copies of the more common A allele. Thus, the 5-HT2B receptor limits degeneration of spinal cord mononuclear phagocytes, most likely microglia, and slows disease progression in ALS. Targeting this receptor might be therapeutically useful.
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http://dx.doi.org/10.1007/s00401-016-1534-4DOI Listing
March 2016

Mice lacking the serotonin 5-HT2B receptor as an animal model of resistance to selective serotonin reuptake inhibitors antidepressants.

Eur Neuropsychopharmacol 2016 Feb 11;26(2):265-279. Epub 2015 Dec 11.

INSERM UMR-S 839, F75005 Paris, France; Université Pierre et Marie Curie, F75005 Paris, France; Institut du Fer à Moulin, F75005 Paris, France. Electronic address:

Depressive disorders are among the most prevalent neuropsychiatric dysfunctions worldwide, with high rates of resistance to antidepressant treatment. Genetic factors clearly contribute to the manifestation of depression as well as to the response to antidepressants. Transgenic mouse models appear as seminal tools to disentangle this complex disorder. Here, we analyzed new key aspects of the phenotype of knock-out mice for the gene encoding the serotonin 2B receptor (Htr(2B)(-/-)), including basal phenotype, ability to develop a depressive-like phenotype upon chronic isolation, and effect of chronic exposure to fluoxetine on chronically stressed Htr(2B)(-/-) mice. We find, here, that Htr(2B)(-/-) mice display an antidepressant-like phenotype, which includes reduced latency to feed in the novelty suppressed feeding test, basal increase in hippocampal BDNF levels, no change in TrkB and p75 protein levels, and an increased preference for sucrose consumption compared to wild type (Htr(2B)(+/+)) mice. Nevertheless, we show that these mice can develop depressive-like behaviors when socially isolated during four weeks. Selective serotonin reuptake inhibitors (SSRI) have been previously shown to be ineffective in non-stressed Htr(2B)(-/-) mice. We evaluated, here, the effects of the SSRI fluoxetine in chronically stressed Htr(2B)(-/-) mice and similarly no behavioral or plastic effect was induced by this antidepressant. All together, these results highlight the suitability to study resistance to SSRI antidepressants of this mouse model displaying panoply of conditions among which behavioral, neurotrophic and plastic causative factors can be analyzed.
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http://dx.doi.org/10.1016/j.euroneuro.2015.12.012DOI Listing
February 2016
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