The Role of Glutamate and Glutamate Receptors in Mouse Models for Emotional Behaviors and Mood Disorders

• Applicants: Professor Dr. Peter Gass; Dr. Rolf Sprengel
• Subject Area: Clinical Psychiatry, Psychotherapy, Child and Adolescent Psychiatry
• Term: from 2007 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 38028095

Recent studies have indicated that the neurotransmitters glutamate is involved in the pathophysiology and treatment of mood disorders. The goal of this proposal is to better understand the role of glutamate in mouse models for affective disorders. We would like to find out to which extent just levels of glutamate (impaired reuptake) are important and how specific alterations of glutamate induced signalling underlies stress-related "disease states" or stress-resistance, respectively. We subject different genetically modified mice with impaired glutamate homeostasis and glutamate signalling to behavioral, neuroendocrinological, molecular and pharmacological studies. A variety of mutant mice with specific deficits in glutmate uptake (EAAT-1 and EAAT-2 transporters) or glutamatergic neurotransmission, e.g. of ionotropic (AMPA- and NMDA-type) glutamate receptors (GluR-A, GluR-C, NR-1, NR-2A) will be analysed. All mice will be subjected to stressinduced depression models (learned helplessness, chronic stress) and a testing battery for emotional behaviors. We will use a step by step approach to test the "glutamate hypothesis" of mood disorders, starting with conventional mutant strains demonstrating the maximum effect of gene deletions (glutamate receptors/transporters genes) on emotional behavior. This will identity those genes that contribute to a behavioral phenotype. We will then identify the brain regions (e.g. hippocampus, forebrain) where the genes of interest are relevant by restricting the gene deletions to specific brain areas. As a proof of concept we will try to rescue specific behavioral phenotypes by a transgenic or alternatively a virus-mediated gene transfer. We will investigate whether glutamatergic drugs that shape emotional behavior in murine depression models have altered effects in mice with genetically depleted glutamate receptors. We will try to identify alterations in molecular/biochemical/cellular signalling pathways that have been postulated for the pathogenesis or pathophysiology of depression. Altogether, these experiments will improve our knowledge of the neurobiologal processes underlying the pathophysiology of mood disorders, and may indicate novel targets for antidepressant therapy.

• DFG Programme: Research Grants