Mice that under- or overexpress glucocorticoid receptors as models for depression or posttraumatic stress disorder.

摘要

Modern molecular and pathophysiological concepts suggest that glucocorticoid receptors (GRs) play a crucial role for the pathogenesis, course and therapy of affective or emotional disorders. Specifically, an impairment of GR signaling has been associated with major depression, whereas overactivity or hyperresponsiveness of GRs have been conceptualized for posttraumatic stress disorder (PTSD). Recently, several research groups have generated transgenic mouse strains that under- or overexpress GRs, respectively. These animals seem to represent valuable tools for studying the foregoing hypotheses. Indeed, first results indicate that mice with a deficit in GR expression show a depression-like behavioral phenotype as well as characteristic neuroendocrinological changes observed in depressive patients. Particularly, GR heterozygous mice with a 50% reduction of GR expression represent a model for combined effects of both genetic and environmental manipulations, since their depression-like behavior becomes only manifest after stress-exposure. Thus, the phenotype of this strain mimics the human situation in depressive disorders, in which individuals at risk are predisposed to develop depressive episodes after stress. It is currently less clear whether, and in which way, mice that overexpress GRs can serve as models for PTSD, or mimic at least specific aspects of the clinical syndrome. The latter strains have still to be subjected to specific tests analyzing conditioning and sensitization processes in fearful situations. So far, mice with compromised GR expression seem to be a good tool to further study molecular, pathophysiological and cellular/structural alterations that underlie specific behavioral features such as despair or helplessness. A major challenge is to decipher which signs and symptoms in patients correspond to these animal behavioral constructs, and to elucidate whether it is possible to gain insights from the animals' response to specific treatments for human therapy.