GENETIC MODEL ROLE NEUROGENESIS ANTIDEPRESSANT RESPONSE

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DESCRIPTION (provided by applicant): Patients with major depression, bipolar disorder and schizophrenia have all been found to have decreased hippocampal volumes, suggesting that decreased hippocampal cell number may be a common endophenotype in multiple mental illnesses. Several classes of psychotropic medications including antidepressants, mood stabilizers and atypical antipsychotics have also been shown to increase neurogenesis in the adult hippocampus. The relationship between adult neurogenesis and the behavioral response to psychotropic medications remains unclear, however recent evidence suggests that generation of new neurons may be critical for antidepressant action. To investigate the role of hippocampal neurogenesis in antidepressant-response we will make use of a novel genetic model for deficits in adult neurogenesis: BF- 1/FoxG1 heterozygous mice. BF-1/FoxG1 is a transcriptional represser that inhibits signaling through the Smad/TGF-beta pathway, and is required for the normal development of the cerebral hemispheres. Mice lacking both copies of the BF-1/FoxG1 gene die shortly before birth (E18.5). Heterozygous BF-1/FoxG1 mice survive, but do not produce new neurons as adults. Thus, these mice offer a genetic model for an endophenotype common to several metal illnesses. To explore the hypothesis that increasing adult neurogenesis is critical for response to antidepressant medications we will treat BF-1/FoxG1 heterozygous mice with different classes of antidepressant medications including tricyclic antidepressants (amitriptyline), serotonin-specific reuptake inhibitors (fluoxetine) and norepinephrine-specific reuptake inhibitors (reboxetine), either subchronically or chronically and characterize both the behavioral response and the effects (if any) on neurogenesis. Preliminary results from these studies should lead to an RO1 proposal aimed at extending these findings. Briefly, follow up studies will extend these studies to other classes of medications including atypical antipsychotics, which may similarly be dependent on adult neurogenesis for their clinical effects. These studies should lead to a better understanding of the mechanism of action of existing antidepressant medications. This, in turn, should allow for a more rational search for new medications for the treatment of depression, and potentially other mental illnesses as well.