Leaky blood-brain barrier in major depressive disorder

Astrocytes and endothelial cells interact to form a properly functional blood-brain barrier. Astrocyte-specific signaling molecules control the blood-brain barrier sealing properties and thus the blood-brain trafficking of various substances passing the border of endothelial cells. Any disruption may lead to brain disorders. A leaky blood-brain barrier is seen in postmortem brains of patients with clinical depression. Women are twice as likely to be affected as men. Intriguingly, the disruption of the blood-brain barrier in female mice induces depression-like behaviors. There is a need to investigate how a leaky blood-brain barrier causes clinical depression in women. This could lead to new personalized treatments. The project Leaky blood-brain barrier in major depressive disorder led by Dr. Kerstin Lenk from the Institute of Neural Engineering at Graz University of Technology and Dr. Barbara Di Benedetto from the University of Regensburg in Germany has two main aims. Firstly, differences in astrocytes and endothelial cells between healthy and diseased human and animal samples will be profiled. Secondly, the team will look at how sex affects the way cells at the blood-brain barrier in depression. Therefore, experimental and theoretical work will be combined. In experiments, 2D and 3D cell culture models will be used to study the blood- brain barrier. The team will use a combination of biomolecular, biochemical, histological, pharmacogenetic, and behavioral tools to identify and manipulate cell-type-specific properties to investigate their contribution to clinical depression. The experimental data will guide the development of computer models including astrocytes, endothelial cells, and the blood-brain barrier, to study the diffusion of molecules between the astrocyte and the blood vessel. The team will share data between labs. Thus, experimental data will be used to fit parameters for the computational models, and results from computational models will be used to refine experiments. Presently, it is unknown whether and how dysfunctional astrocytes, dysfunctional endothelial cells, or both contribute to the onset of clinical depression, how they may influence blood- brain barrier formation, and the exact cell types targeted by therapeutic drugs.