Team 5 : Serotonin signaling in plasticity and disease (Maroteaux)

Team leader : Luc Maroteaux (DR1 CNRS)

Major aims

Serotonin (5-hydroxytryptamine, 5-HT) has been proposed to modulate morphogenetic activities, including neural differentiation, axon outgrowth, or synaptic plasticity. 5-HT is known to modulate a wide range of physiological functions inside and outside the central nervous system. 5-HT has been implicated in the regulation of several cardiovascular and psychiatric disorders. More than 20 years ago, our group has shown that some of the morphogenetic actions of 5-HT involved 5-HT2 receptors. By a combination of genetic ablation and pharmacological ablation, we previously established a role of 5-HT via 5-HT2B receptors (i) in cardiac development and in left ventricular systolic function in adult mice, (ii) in pathogenesis of pulmonary hypertension and (iii) in valvulopathy. These functional investigations on 5-HT developmental/physiological functions are now being completed and extended by molecular and physiopathological approaches at the brain level with a particular interest for psychiatric diseases.

The work of our group is concerned with the control of plasticity in the adult nervous system and its pathological and pharmacological alterations. As a world expert in the study of the 5-HT2B serotonin receptor, after having made major contributions to the demonstration of the role of this receptor in the cardiovascular system, we have moved our interest in characterizing its function in the brain. During the past years, our research group has successfully demonstrated a previously unsuspected role of 5-HT2B receptor in the nervous system. We have participated in a collaborative effort to demonstrate that a loss of function SNP in the 5-HT2B receptor gene (HTR2B) was associated with psychiatric diseases marked by high impulsivity and suicidal behavior in humans. We showed that Htr2B−/− mice displayed also increased impulsive behaviors, in particular in delayed discounting tasks. We have also shown that these receptors contribute to the behavioral and physiological effects of amphetamine derivatives and 5-HT releasers. We then evidenced the need for these receptors for the antidepressant effects of SSRIs as a positive serotonergic autoreceptor.

Serotonin tone contributes to the balance between behavioral inhibition and disinhibition. Serotonin and dopamine interact across neuronal circuits in an apparent opposite fashion to modulate aspects of both impulsive and compulsive responding by as yet poorly identified brain-based systems. Central serotonin function is thought to be a critical component of behavioral inhibition or impulse control and in the regulation of impulsive aggressive behavior. A shift from impulsivity to compulsivity occurs during the development of addictive behavior. Psychiatric disorders such as obsessive compulsive disorder, attention deficit hyperactivity disorder, anti-social behavior and addictive behavior are all characterized by changes or abnormalities in impulse control and display also a strong dopamine contribution.

Upon peripheral infection, many of these functions are deregulated, causing an "illness syndrome", or "sickness behavior", which resembles a transient depression. Moreover, following a peripheral inflammation, microglia (brain macrophages) are rapidly activated and secrete inflammation mediators. Recent studies have shown links between microglial activation and psychiatric pathologies, particularly in the case of depression. However, the role of microglia in the control of behavior is not established, and it is also unclear how microglial activation is controlled in these pathologies. Finally, although many clinical studies suggest links between inflammation and psychiatric disorders, few markers have been identified that allow us to categorize patients according to their inflammatory state. Our team demonstrated that microglia express a receptor for serotonin, the 5-HT2B receptor encoded by the gene Htr2b. This receptor is also expressed in the brain stem neurons that produce serotonin. A recent collaboration of the team showed the involvement of this receptor in microglia survival in a model of amyotrophic lateral sclerosis. On the other hand, our data show that mice invalidated for the gene encoding this receptor have exacerbated and prolonged sickness behavior (weight loss, body temperature variation, decreased grooming). Invalidation of Htr2b specifically in microglia reproduces this phenotype, demonstrating the role of microglia. Microglia in Htr2b-/- mice differ from those of wild-type mouse in their activation state, indicating that the 5-HT2B receptor modulates the microglial response and suggesting a protective role of this receptor against excessive neuroinflammation. We suggest that the serotonin-microglia interaction controls neuroinflammation and illness behavior, and that deregulation of this pathway is involved in some psychiatric disorders.

Our work now intends to unravel links between the serotonin and dopamine system in relation to impulsivity, compulsivity and addiction and to identify the cellular basis of these actions (dopamine and/or serotonin neurons and/or microglia).

Main questions to be addressed

During the past years, we have progressed in our understanding of molecular mechanisms initiated by 5-HT2B receptors using cell and animal models.

• Role of presynaptic 5-HT2B receptors in the positive regulation of serotonin neurons: a contributor to anxiety and depression? The genetic or pharmacological inactivation of this receptor eliminates behavioral and neurogenic effects of antidepressant SSRIs, clearly implicating 5-HT2B receptors in presynaptic 5-HT homeostasis. The 5-HT2B receptor appears therefore, as a positive modulator of serotonergic activity and may, thus, give clues in the search for new targets in the development of antidepressants.

• Role of postsynaptic 5-HT2B receptor in the responses of dopamine neurons: a link between impulsivity and addiction? Recent evidence indicates that 5-HT2B receptor haplotypes, which correspond to lower receptor expression, segregate with the cocaine abuse phenotype. These findings support again in Humans our finding in mice that this receptor inactivation favors addictive behaviors. These initial results underpin the importance of 5-HT2B receptors in addiction.

• Role of 5-HT2B receptor in neuroinflammation: microglia as new targets of the serotonergic system in psychiatric disorders? The recent discovery in our laboratory of 5-HT2B receptor expression by microglia, point to the hypothesis that microglia could interact with the 5-HT system to regulate central responses to peripheral inflammation in adult, and some steps of brain development, both of which will be assessed during the proposed work.

Together these studies should identify the link between impulsivity/addiction/psychosis, and the relevant pathways (dopamine or serotonin neurons and/or microglial cells) and thus contribute to precisely define the role of 5-HT2B receptors in the control of 5-HT and/or DA levels in the activity of these neurons or in the trophic action of microglia.

Team Members

Team leader: Luc Maroteaux (DR1 CNRS, PhD Strasbourg)

  • Anne Roumier, MCU UPMC
  • Catherine Béchade, CR1 INSERM
  • Imane Moutkine, IE INSERM
  • Ivana d'Andrea, Post-doc
  • Emily Quentin, PhD student UPMC

Former members:

  • 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 UPMC
  • Sophie Mahieu, Post-doc INSERM
  • Marta Kolodziejczak, PhD student UPMC