DEVANX

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

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 Obiettivo del progetto (Objective)

'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'

Introduzione (Teaser)

New research has revealed some of the underlying environmental, behavioural and biological factors behind anxiety. The condition affects countless individuals and it has come to represent an economic burden in terms of sick leave taken from work.

Descrizione progetto (Article)

Scientists have known for a long time that two brain hormones, gamma-aminobutyric acid (GABA) and serotonin, play a role in anxiety. It has recently come to light that environmental risk factors may affect serotonin-related genes, and that GABA receptors play an important role in mediating the anxiety-countering effects of GABA. It is also now known that these two hormonal systems interact, but deeper insights are needed if targeted therapies are to be developed.

Specialists in development, neuronal plasticity, neurobehaviour, neuropharmacology and mouse genetics came together under the EU-funded 'Serotonin and Gaba-B receptors in anxiety: From developmental risk factors to treatment' (DEVANX) project to gain further related insights. They focused on how GABA and serotonin systems interact in the developmental programming of anxiety.

Project researchers fully characterised various mouse models, including some that were deficient in serotonin or certain GABA receptor activities. They were able to determine the role of two GABA receptors, GABAb1A and GABAb1B, as well as the implication of specific hippocampal circuits involved in remembering anxiety-causing stimuli.

The team also validated new genetic methods to examine serotonin circuits. They found that pharmacogenetic approaches worked well to tease apart anxiety-related circuits.

A number of scientific publications have been published relating to this research, pointing to the massive contribution the DEVANX project has made to the field. A better understanding of the mechanisms driving anxiety could lead to novel therapeutic approaches.