Retinoic Acid Homeostasis in Major Depression

• Applicant: Dr. Julian Hellmann-Regen
• Subject Area: Biological Psychiatry ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 271300457

With this revised first time application, the applicant applies for his own temporary position and proposes a project to elucidate a role for retinoic acid (RA) homeostasis in the pathogenesis of major depression (MD).MD is a severely debilitating, often chronic psychiatric disorder and a major cause of morbidity worldwide. Therapeutic options available are still far from optimal and the pathogenetic mechanisms are still far from clear. Recently, a role for RA in the pathogenesis of major depression has been suggested (Bremner et al., 2012).RA represents the biologically most active form of Vitamin A and plays a critical role not only in the developing, but also the adult brain, where it is implicated in the modulation of neuronal differentiation, synaptic plasticity, neuroinflammation, the HPA axis as well as neuropeptide- and dopaminergic neurotransmission. Moreover, RA plays a role in hippocampus-based learning and exhibits potent neuroprotective effects. Interestingly, all of these diverse processes have been linked to the pathogenesis of major depression. Similarly, most of these processes are affected by several clinically established antidepressant drugs, a fact that has usually been interpreted as additional, pleiotropic mechanisms of action. Local brain RA concentrations are the resultant of a homeostatic balance between local RA synthesis and RA degradation. This process is termed RA homeostasis. The association of RA with diverse processes typically altered in MD highlights the potential of RA to bridge a gap between at first glance diverse theories on the pathogenesis of major depression. Own preliminary data demonstrating a strong direct, enhancing effect of the antidepressant fluoxetine on local brain RA metabolism further emphasize this assumption.Therefore, we hypothesize that RA homeostasis is disturbed in major depression. As a result, we hypothesize thatA) peripheral RA serum levels will be altered in unmedicated depressed patients compared with healthy controlsB) RA homeostasis will be altered as a depression-specific trait in PBMC-derived primary cells from depressed patients.Moreover, we hypothesize that C) traditional antidepressant drugs will target RA metabolism as part of their pleiotropic mechanism of action and enhance local brain RA concentrations in a region-specific manner.These hypotheses will be tested in the proposed project by pursuing a clinical and a preclinical subproject: The clinical subproject will involve the recruitment of 64 unmedicated patients suffering from major depression and 64 healthy controls. Individual endogenous RA serum concentrations as well as functional RA homeostasis parameters in individual PBMC-derived primary cell cultures will be experimentally assessed using previously established methodology. In the preclinical subproject, the hypothesized drug-effects on local brain RA distribution will be assessed using murine brain tissue and transgenic RA-reporter mice.

• DFG Programme: Research Grants