| Autor: |
Herzog DP; Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany.; Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany., Pascual Cuadrado D; Institute of Physiological Chemistry, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany., Treccani G; Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany.; Institute of Microscopic Anatomy and Neurobiology, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany., Jene T; Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany.; Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany., Opitz V; Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany., Hasch A; Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany., Lutz B; Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany.; Institute of Physiological Chemistry, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany., Lieb K; Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany.; Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany., Sillaber I; Genevention GmbH, Göttingen, Germany., van der Kooij MA; Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany.; Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany., Tiwari VK; Institute of Molecular Biology, Johannes Gutenberg University Mainz, Mainz, Germany.; Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queens University Belfast, Belfast, UK., Müller MB; Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany. marianne.mueller@uni-mainz.de.; Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany. marianne.mueller@uni-mainz.de. |
| Abstrakt: |
Major depressive disorder is the most prevalent mental illness worldwide, still its pharmacological treatment is limited by various challenges, such as the large heterogeneity in treatment response and the lack of insight into the neurobiological pathways underlying this phenomenon. To decode the molecular mechanisms shaping antidepressant response and to distinguish those from general paroxetine effects, we used a previously established approach targeting extremes (i.e., good vs poor responder mice). We focused on the dentate gyrus (DG), a subregion of major interest in the context of antidepressant mechanisms. Transcriptome profiling on micro-dissected DG granule cells was performed to (i) reveal cell-type-specific changes in paroxetine-induced gene expression (paroxetine vs vehicle) and (ii) to identify molecular signatures of treatment response within a cohort of paroxetine-treated animals. We identified 112 differentially expressed genes associated with paroxetine treatment. The extreme group comparison (good vs poor responder) yielded 211 differentially expressed genes. General paroxetine effects could be distinguished from treatment response-associated molecular signatures, with a differential gene expression overlap of only 4.6% (15 genes). Biological pathway enrichment and cluster analyses identified candidate mechanisms associated with good treatment response, e.g., neuropeptide signaling, synaptic transmission, calcium signaling, and regulation of glucocorticoid secretion. Finally, we examined glucocorticoid receptor (GR)-dependent regulation of selected response-associated genes to analyze a hypothesized interplay between GR signaling and good antidepressant treatment response. Among the most promising candidates, we suggest potential targets such as the developmental gene Otx2 or Htr2c for further investigations into antidepressant treatment response in the future. |
