Serotonin and GABA-B receptors in anxiety: from developmental risk factors to treatment. (DEVANX)
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 are the focus of this project.
GABAergic and serotoninergic systems are key players in the control of anxiety states but the precise base for their action has remained elusive. New findings, brought about by members of this consortium, suggest a developmental role of serotonin (5-HT) and environmental risk factors in the genesis of anxiety disorders. Metabotropic GABA-B receptors play a critical role in mediating the anxiolytic effects of GABA and have strong reciprocal interactions between with serotonin systems in the genesis of anxiety disorders. The proposal will bring new knowledge on the neurobiological basis of anxiety, and open up novel therapeutic approaches in anxiety disorders.
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.
The research group at the Universidad Pablo de Olavide is leader of WP5: GABA-B receptors and development. The team is a recognized specialist for in vivo electrophysiology in the field of associative learning and brings unusual expertise in in vivo behaving mouse electrophysiology. Recent studies from this group were able to demonstrate the existence of functional changes (activity-dependent synaptic plasticity) in the hippocampal circuits in vivo, while the animal is acquiring a conditioned response.
Dr. Agnès Gruart i Massó (female), PhD, has more than 15 years of experience on the activity of cortical and subcortical circuits underlying motor control and acquisition of new motor abilities. Recently, she contributed to the development of sophisticated electrophysiological techniques that allow the study of activity-dependent synaptic events in cortical circuits during acquisition, extinction, recall, and retrieval, of learning processes. She will design selected behavioral tests, together with unitary and field electrophysiological recording techniques, aimed to analyze whether these learning processes are modified in genetically-modified mice. She will co-ordinate the research carried out in Seville.
Dr. José M. Delgado-García (male), MD, PhD director of the Division of Neurosciences. Prof. Delgado-García has more than 30 years of experience in studies of motor control (oculomotor, respiratory, facial, hypoglossal) systems and on neural pre-motor circuits involved in the acquisition of new motor abilities. He has recognized experience in electrophysiological studies in alert behaving mammals during reflex, voluntary and learned motor responses, involving cortical, and subcortical structures (J. Neurosci., Neuron, PNAS.). He will analyse anxiety-dependent synaptic changes in hippocampal (perforant pathway-DG-CA3-CA1) circuits of transgenic 5-HT vs. wild-type mice.
- Measurement of the impact on anxiety phenotypes of altering brain levels of 5-HT at different times in development and in different areas of the brain.
- Identification of the neuronal circuits that mediate the effects of the 5-HT1A receptor during the maturation of anxiety networks with a focus on the hippocampus, amygdala, and raphe nuclei.
- Study of the role of 5-HT on the maturation and function GABAergic systems in anxiety circuits.
- Study of alterations in anxiety following genetic or pharmacological manipulations of GABA-B receptors effect - Exploration of the developmental role of GABA-B receptors in sculpting the anxiety circuits.
- Design of new strategies for treating anxiety with GABA-B receptor modulators
- Assessment of the role of 5-HT and GABA-B in the modulation of early environmental risk factors for anxiety
The project will provide new information to better understand the neurobiological underpinnings of brain dysfunction in anxiety disorders. The research effort of the consortium will provide insights on the genetic and environmental determinants of these affective diseases and how these two major risk factors interact to generate the illness. The ultimate objective is to provide new knowledge which can be used by the participants and by pharmaceutical companies based in Europe to develop new drugs for the treatment of anxiety.
Laboratorio de Neurociencia
Code PAIDI: BIO 122
Agnès Gruart i Massó. Socio.
Universidad Pablo de Olavide
Budget of Andalusian group: € 447,465.60
- Universidad Pablo de Olavide (Spain)
- Institut Fer à Moulin, Paris (France)
- Hôpital Salêtrière, Paris (France)
- Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo (Italy)
- Institute of Physiology, Department of Biomedicine, University of Basel (Switzerland)
- School of Pharmacy, Department of Pharmacology & Therapeutics, University College Cork, Cork (Ireland)
- Central Institute of Mental Health, J5 Mannheim (Germany)