Human Cell Culture Model for Fast-Scan Cyclic Voltammetry Measurements to Study Depression and Neuroinflammation

Major depressive disorder (MDD) poses a huge toll on health systems around the world and a significant number of patients show resistance towards classic antidepressants. Recently, evidence in the rodents suggest that neuroinflammation may underlie chemical changes in the brain experienced during depression, namely an inverse relationship between histamine, associated with inflammation, and serotonin. We previously found that this relationship could be pharmacologically restored via a combination of agents targeting the histaminergic and serotonergic system. In seeking to expand this work to humans we turn to human induced pluripotent stem cells (iPSCs)-derived model systems. These cell culture models are a powerful tool to study human pathologies, including depression, especially with respect to drug development and high-throughput testing. Here, we established an iPSC-derived 3D spheroid model containing serotonergic neurons or a combination of neurons and microglia to study neuroinflammatory processes in a bid to mimic in vivo neuroinflammation. First, we adapted fast scan cyclic voltammetry (FSCV) and fast-scan controlled adsorption voltammetry (FSCAV) measurements at carbon fiber micro-electrodes (CFMs) to this in vitro system. We then analysed serotonin levels upon external electrical stimulation of the spheroid and were able to show dynamic changes by release and reuptake similar to in vivo profiles. This underlines the validity of our spheroid system to model processes in the living brain. Next, we added microglia to the system, and activated the microglial immune response by treatment with lipopolysaccharide (LPS). FSCV and FSCAV signals were compared to in vivo signals to determine whether the serotonin-histamine-correlation is replicable. In the future, applicability of this platform for drug development will be tested. The possibility to up-scaling cell culture even holds the possibility for future high-throughput screens of novel antidepressants.