DEVANX · Serotonin and GABA-B receptors in anxiety : from developmental risk factors to treatment

GABAergic and serotoninergic systems are key players in the control of anxiety states but the precise bases for their action has remained elusive. New findings, brought about by members of this consortium, are radically changing our views on the neurobiological action of these two transmitters and will be the focus of the present proposal. The first original dimension is the discovery of a developmental role of serotonin (5-HT) in the genesis of anxiety disorders, and the finding of interactions between 5-HT-related genes and environmental risk factors. The second new dimension is the discovery that metabotropic GABA-B receptors play a critical role in mediating the anxiolytic effects of GABA, a starting point for the conception and design of novel therapeutic approaches. Finally, recent evidence point to strong reciprocal interactions between the two systems. In this proposal , researchers that are at the forefront of these research domains will build on and extend these promising new findings. The project associates specialists of development, neuronal plasticity, neurobehaviour, neuropharmacology and mouse genetics. The consortium will explore the neuronal circuits mediating the developmental effects of 5-HT by using existing models and by creating new models for site- and time-specific invalidation of 5-HT related genes (Tph2, pet1,VMAT2,5-HT1A-R), focusing on the hippocampus, amygdala and raphe nuclei. They will explore the role of GABA-B receptors in anxiety and the interaction of these receptors with the 5-HT system. The developmental effects of GABA-B receptors and a new generation of GABA-B modulators that produce anxiolytic effects in animal models will be explored. Finally they will investigate how exposure to adverse environments interacts with 5-HT-genes and GABA-B receptor genes to produce anxiety phenotypes. The proposal will bring new knowledge on the neurobiological basis of anxiety, and open up novel therapeutic approaches in anxiety disorders