Human Midbrain Organoids for In Vitro Modeling of Parkinson ’ s Disease

The sodium concentration of astrocytes is classically viewed as being kept under tight homeostatic control and at a relatively stable level under physiological conditions. Indeed, the inward electrochemical gradient for sodium, generated by the Na+/K+ -ATPase, is a prerequisite for their highly negative membrane potential and a central element in energizing membrane transport. As such it is tightly coupled to the homeostasis of other ions and to the reuptake of transmitters such as glutamate. Consequently, it might be expected that sodium ions entering astrocytes are directly expelled again, protecting the cells from a reduction in the sodium driving force and an attenuation of sodium-dependent processes. Recent studies, however, have demonstrated that this picture is far too simplistic. Research from our and other laboratories has provided compelling evidence that the intracellular sodium concentration in astrocytes undergoes significant changes with neuronal activity. The amplitude and spatial distribution of glial sodium transients depend on the level of activity and the number of activated synapses: it can be local and restricted to single processes, but also include global sodium changes that invade the soma and even neighboring astrocytes. Activity-induced sodium transients are surprisingly long-lasting and show properties that are distinctly different from those of calcium signals. Because sodium is not buffered, sodium transients generated by sodium-dependent glutamate uptake are linearly related to a wide range of neuronal activity. Sodium transients hence represent direct and unbiased intracellular indicators of neuronal glutamatergic activity, which are transmitted to the astrocyte network. From these studies, it emerges that sodium homeostasis and signaling of astrocytes are two sides of the same coin: sodium-dependent transporters, primarily known for their role in ion regulation and homeostasis, also generate relevant ion signals during neuronal activity. The functional consequences of activity-related sodium transients are manifold and are just coming into view, enabling new insights into astrocyte function and neuron-glia interaction in the brain. The talk will highlight current knowledge about the mechanisms that contribute to sodium homeostasis in astrocytes, present recent data on the spatial and temporal properties of glial sodium signals and discuss their functional consequences under physiological and pathophysiological conditions. MOLECULAR and CELLULAR NEUROSCIENCE