Serotonin, microglia, plasticity and disease
Our group is interested in the control of neuronal plasticity in the central nervous system and its pathological and pharmacological alterations. Functional neural circuits rely on a sophisticated balance between developing synapses and eliminating redundant or inappropriate neural connections. Schizophrenia and autism spectrum disorders are neurodevelopmental disorders characterized by disturbances in brain connectivity that cause a range of symptoms, including cognitive and social deficits. It has been hypothesized that these pathologies arise in part due to deficits in pruning the synapses, thus producing aberrant circuits. Recent studies have highlighted links between activation of microglial cells, resident macrophages of the brain, and psychiatric pathologies, in particular depression, schizophrenia or autism. However, the role of microglia in controlling behavior has not been established, and it is unclear how microglial activation is modulated in these pathologies.
Over the past few years, our research group has demonstrated an unexpected role for a serotonin receptor, 5-HT2B, in the central nervous system. We have shown that loss of function mutations in the 5-HT2B receptor gene are associated with psychiatric diseases marked by high impulsivity and suicidal behavior in humans, and that mice knocking out for this receptor also exhibit impulsive behavior. After having demonstrated that the 5-HT2B receptor was expressed by neurons in the brainstem that produce serotonin, we uncovered the need for this receptor for the antidepressant effects of the selective serotonin reuptake inhibitors (SSRIs), blockers of the serotonin transporter SERT, as well as its function positive serotonergic autoreceptor. The genetic or pharmacological inactivation of this receptor eliminates the behavioral and neurogenic effects of SSRI antidepressants, clearly implicating the presynaptic 5-HT2B receptors in serotonergic homeostasis. The 5-HT2B receptor therefore appears to be a positive modulator of serotonergic activity and its study can thus give clues to the search for new targets in the development of antidepressants.
More recently, we have discovered that microglia mainly express this serotonin receptor: the 5-HT2B receptor modulates the motility of microglial extensions as well as the expression of markers of inflammation in the brain after peripheral inflammation; the early absence of expression of this receptor specifically in microglia is associated with behavioral alterations. This discovery in our laboratory of the expression of the 5-HT2B receptor by microglia, supports the hypothesis that microglia could interact with the serotonergic system to regulate central responses to peripheral inflammation in adults, certain stages of development of the brain, and thus regulate its connectivity.
On the other hand, schizophrenia is highly hereditary, and genome-wide association studies have shown that the major histocompatibility complex has the greatest genetic association with schizophrenia. In particular, the complement C4, which is located in this locus, is associated with schizophrenia since specific mutations which cause an increased expression of C4 confer a greater risk for this pathology. We are interested in understanding the role of a key protein in the immune system, the C4 complement, in brain damage that is associated with schizophrenia. We are studying in particular the implication of C4 in glia-neuron interactions and synaptic transmission. In the longer term, these results can be used to identify new drug targets and thus develop new therapeutic strategies.
Main questions to be addressed
In recent years, we have progressed in understanding the molecular mechanisms initiated by the activation of serotonin receptors and / or microglia thanks to cell models and transgenic mice. Our work in progress is focused on:
•Role of presynaptics of 5-HT2B receptors in the upregulation of serotonin neurons: contribution to anxiety and depression? The excess inhibitory control exerted by the 5-HT1A receptors in the absence of 5-HT2B receptors may explain the lack of behavioral response to SSRIs. Our recent results, which reveal the 5-HT2B receptor as a direct positive regulator of serotonergic neurons, support the hypothesis that the 5-HT2B receptors control the excitability of these neurons counteract the negative action of the 5-HT1A/1B receptors and thus participate in the homeostasis of the serotonergic system. Our work seeks to elucidate the molecular mechanisms involved.
• Role of the 5-HT2B receptor in neuroinflammation: the microglia new targets of the serotonergic system in psychiatric disorders? We propose to test the hypothesis that inflammation, and in particular an abnormal activation of microglia during critical postnatal periods, is a factor of sensitivity to psychiatric disorders. This work should indicate how the interactions of the gene (mutation) and the environment (infection) can determine susceptibility to psychiatric disorders.
• Role of the C4 complement in schizophrenia: the microglia new therapeutic targets? Previous work has shown that mice deficient in various complement proteins have a reduced size of synaptic terminations during development, supporting that C4 exerts its effects by activating the complement cascade. We propose that there is a critical development window during which the prefrontal cortical circuits are sensitive to alterations in C4 expression, thus opening up the possibility of early therapeutic intervention to modify the development trajectory of schizophrenia.
Together, these studies should make it possible to determine the link between autism/depression/psychosis, and the relevant pathways (serotonin, neuron subtypes and/or microglial cells) and thus help to define precisely the role of serotonin and microglia in the connectivity and activity of these neurons.
Co-leaders: Anne Roumier (Professor, Sorbonne University) and Corentin Le Magueresse (CR1 INSERM)
- Luc Maroteaux (DR1 CNRS)
- Catherine Béchade, CR1 INSERM
- Célia Delhaye, PhD student Sorbonne Univ
- Nayadoleni Nieves-Rivera, PhD student Sorbonne Univ
- Emilie Turlure, PhD student Sorbonne Univ
- Imane Moutkine, IE INSERM
- Giulia Albertini, Post-doc INSERM
- Mélanie Druart, Post-doc INSERM
- Amina Benhadda, PhD student Sorbonne Univ
- Fanny Etienne, PhD student Sorbonne Univ
- Emily Quentin, PhD student Sorbonne Univ
- Pothitos Pitychoutis, Post-doc INSERM (PhD Athens, Greece)
- Silvina Diaz, Post-doc DIM STEM (PhD Buenos-Aires Argentina)
- Stéphane Doly, Post-doc (Doctorat UPMC, Paris)
- Sarah Rogan, MD-PhD student, Univ. North Carolina, Bourse Chateaubriand
- Arnaud Belmer, PhD student Sorbonne Univ
- Sophie Mahieu, Post-doc INSERM
- Marta Kolodziejczak, PhD student Sorbonne Univ
Most Recent Publications
First quantitative dosages: Strong correlations between non-5-HT2Rs serotonin receptors on normal human heart valves
Schussler O, Maroteaux L, Jashari R, Falcoz P, Alifano M, Lecarpentier Y, Launay JM
Front Cardiovasc Med. 2022 Oct 25;9:897657.
Targeting the brain 5-HT7 receptor to prevent hypomyelination in a rodent model of perinatal white matter injuries
Bokobza C, Jacquens A, Guenoun D, Bianco B, Galland A, Pispisa M, Cruz A, Zinni M, Faivre V, Roumier A, Lebon S, Vitalis T, Csaba Z, Le Charpentier T, Schwendimann L, Young-Ten P, Degos V, Monteiro P, Dournaud P, Gressens P, Van Steenwinckel J.
J Neural Transm (Vienna). 2022 Nov 6.
Elevated expression of complement C4 in the mouse prefrontal cortex causes schizophrenia-associated phenotypes
Druart M, Nosten-Bertrand M, Poll S, Crux S, Nebeling F, Delhaye C, Dubois Y, Mittag M, Leboyer M, Tamouza R, Fuhrmann M, Le Magueresse C.
Mol Psychiatry. 2021 Jul;26(7):3489-3501.
Serotonin 2B Receptor by Interacting with NMDA Receptor and CIPP Protein Complex May Control Structural Plasticity at Glutamatergic Synapses
Benhadda A, Quentin E, Moutkine I, Chanrion B, Russeau M, Marin P, Levi S, Maroteaux L
ACS Chem Neurosci. 2021 Apr 7;12(7):1133-1149.
Targeting 5-HT2B Receptor Signaling Prevents Border Zone Expansion and Improves Microstructural Remodeling After Myocardial Infarction
Snider JC, Riley LA, Mallory NT, Bersi MR, Umbarkar P, Gautam R, Zhang Q, Mahadevan-Jansen A, Hatzopoulos AK, Maroteaux L, Lal H, Merryman WD
Circulation. 2021 Mar 30;143(13):1317-1330.
International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function
Barnes NM, Ahern GP, Becamel C, Bockaert J, Camilleri M, Chaumont-Dubel S, Claeysen S, Cunningham KA, Fone KC, Gershon M, Di Giovanni G, Goodfellow NM, Halberstadt AL, Hartley RM, Hassaine G, Herrick-Davis K, Hovius R, Lacivita E, Lambe EK, Leopoldo M, Levy FO, Lummis SCR, Marin P, Maroteaux L, McCreary AC, Nelson DL, Neumaier JF, Newman-Tancredi A, Nury H, Roberts A, Roth BL, Roumier A, Sanger GJ, Teitler M, Sharp T, Villalón CM, Vogel H, Watts SW, Hoyer D.
Pharmacol Rev. 2021 Jan;73(1):310-520.
The serotonin 2B receptor is required in neonatal microglia to limit neuroinflammation and sickness behavior in adulthood
Béchade C, D’Andrea I, Etienne F, Verdonk F, Moutkine I, Banas SM, Kolodziejczak M, Diaz SL, Parkhurst CN, Gan WB, Maroteaux L, Roumier A.
Glia. 2021 Mar;69(3):638-654.
An Etiological Foxp2 Mutation Impairs Neuronal Gain in Layer VI Cortico-Thalamic Cells through Increased GABAB/GIRK Signaling
Druart M, Groszer M, Le Magueresse C.
J Neurosci. 2020 Oct 28;40(44):8543-8555.
Regulation of microglia by neuromodulators: Modulations in major and minor modes.
Albertini G, Etienne F, Roumier A.
Neurosci Lett. 2020 Apr 25:135000.
Serotonin (5-HT) Shapes the Macrophage Gene Profile through the 5-HT2B-Dependent Activation of the Aryl Hydrocarbon Receptor.
Nieto C, Rayo I, de Las Casas-Engel M, Izquierdo E, Alonso B, Béchade C, Maroteaux L, Vega M, Corbí Á.
J Immunol. 2020 May 15;204(10):2808-2817.