Work Package 4
Cellular stress and mitochondrial perturbation in affective disorders
Prof. Dr. Carsten Culmsee
University of Marburg, Institute for Pharmacology and Clinical Pharmacy, Biochemical-Pharmacological Centre Marburg
Affective disorders such as major depressive and bipolar disorder are among the most prevalent forms of mental illness. These mood disorders are highly complex diseases and their aetiologies involve complex interactions of genetic and environmental factors. Despite intensive research over the past years, the cellular and molecular mechanisms driving the development of affective disorders are still largely unknown. Multiple lines of evidence, including clinical, genetic, and experimental studies, support the involvement of mitochondria in the pathophysiology of MDD and BD. Here, we address the question whether genetic risk in combination with environmental factors, such as maltreatment, affect neuronal mitochondrial integrity and function, thereby altering brain energy resources and, thus, the vulnerability for depression. Further, it is tested whether the genetic risks can be overcome by beneficial environment or pharmacological protection of mitochondrial performance. These central questions are approached in a translational setting using patient samples, samples from animal models and cultured cells. In particular, we investigate neurobiological mechanisms at the level of mitochondria in patients’ blood mononuclear cells (PBMC), samples from transgenic rat model systems (CACNA1C+/- and NCAN+/-) and in hippocampal neuron culture models where mutations in CACNA1C and NCAN are combined with cellular stress. The investigated emerging determinants of cellular and subcellular stress are alterations of mitochondrial integrity and function, formation of reactive oxygen species (ROS) and intracellular Ca2+ ([Ca2+]i) deregulation. These studies also include the impact of neuroinflammatory responses as a major hallmark of intercellular stress responses in settings of G x E interactions in vitro, and in the transgenic rat models (CACNA1C+/-, NCAN+/- and wildtype rats exposed to standard housing, maltreatment or beneficial environment). Further, the impact of microRNA regulation on pathological alterations in mitochondria is investigated. Similar neurobiological determinants of stress signalling and mitochondrial dysfunction are assessed in patient samples and may serve as pathophysiological indicators, markers for course of illness, subgrouping of patients for longitudinal course and, in the future, for evaluation of therapeutic intervention. Finally, therapeutic approaches directed against mitochondrial pathways of cellular stress are applied in vitro and in vivo in order to evaluate protecting mitochondria as a feasible approach to attenuate or even reverse the combined effects of the genetic and environmental determinants in affective disorders. Overall these studies provide new insights into the neurobiology of affective disorders and novel therapeutic targets at the subcellular level with potential relevance for future treatment strategies.