The role of glutamate and glutamate receptors in mouse models for emotional behaviors and mood disorders
The neurotransmitter glutamate is involved in the pathophysiology and treatment of mood disorders. The goal of our studies is to dissect the role of glutamate in mouse models for affective disorders. We subject different genetically modified mice with impaired glutamate homeostasis and glutamate signaling to behavioral, neuroendocrinological, molecular and pharmacological studies. A variety of mutant mice with specific deficits in glutamate 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. By restricting the gene deletions to specific areas in the brain we will identify the relevant brain regions. Glutamatergic drugs that shape emotional behavior in murine depression models will also be tested in these mice.
Alterations in molecular/biochemical/cellular signaling pathways that have been postulated for the pathogenesis or pathophysiology are investigated.
Functional changes in neuronal networks in mice with selective loss of AMPA or NMDA receptors We have developed viral-mediated gene expression systems for rapid and precise delivery of proteins, including genetically-encoded fluorescent calcium indicator proteins (FCIPs), into neurons for recording activity at a population scale. Our goal is to characterize by optical imaging spatiotemporal activity pattern of a group of neurons activated by sensory experience.
Fig.2: The gene for the NMDA receptor subunit NR1 is specifically removed in the Gyrus dentatus of the hippocampus.
(A) The expression of Cre recombinase is restricted to the granular cells of the Gyrus dentatus by the CamK2A/Grin2C promoter which controls the transcription factor (itTA) that is needed for Cre expression. In Cre expressing cells the gene segments which are flanked by loxP sites (black triangles) are removed.
The loss of intact NR1 expression in the Gyrus dentatus region can be monitored by in situ hybridisation (B) or by anti-NR1 antibodies in immunocytochemical stainings (C, lower pannels). (C, upper pannels) The Gyrus dentatus specific Cre expression is visualized by anti-Cre antibodies which show a strong labeling of the granular cell layer.