Counteracting Neuronal Alterations in Space and on Earth. Novel Hydroxynorkeamine Derivatives are Potent Agents to Enhance Synaptic Plasticity in vitro

Abstract

During spaceflight, humans experience a variety of physiological changes due to deviations from accustomed Earth conditions. Specifically, the lack of gravity is responsible for many effects observed in returning astronauts. These impairments can include structural as well as functional changes of the brain and a decline in cognitive performance. However, the underlying physiological mechanisms remain elusive. Alterations in neuronal activity play a central role in neurological disorders and altered neuronal transmission may disturb human cognitive function and thus diminish performance in space. Accordingly, understanding the influence of altered gravity on neuronal activity on the cellular and network level is of high relevance. Neuronal cells are known to be sensitive to influences of altered gravity. By using multi-electrode array (MEA) technology, we advanced electrophysiological investigations covering single-cell to network level responses during exposure to decreased (micro-) or increased (hyper-) gravity conditions. Integration of the MEA device into a custom-built environmental chamber allowed us to conduct experiments on various large gravity research platforms including the DLR human centrifuge, the ZARM drop tower and the MAPHEUS sounding rocket. Here, the spontaneous activity of in vitro human induced pluripotent stem cell (hiPSC)-derived neural networks was recorded in real time. Our data demonstrate that alterations in gravity levels trigger changes in neuronal activity. Hypergravity exposure led to an initial reduction in spiking frequency which was compensated within a minute time range. Upon onset of microgravity, the mean action potential frequency across the neural networks was significantly enhanced and further compensated even below 1g baseline values after less than one minute. Furthermore, neuronal networks especially reacted to acute changes in mechanical loading (hypergravity) or unloading (microgravity). The current study clearly shows the gravity-dependent response of neuronal networks endorsing the importance of further investigations of neuronal activity and its adaptive responses to micro- and hypergravity including transition phases.