Experiments employing sequential transfer of cell culture media from microglia to astrocytes or vice versa indicate that astrocytes can act as amplifiers of microglia-derived mediators in the production of neurotoxic factors. Collectively, our data are consistent with a model in which LPS-induced expression of factors such as IL1β and TNFα by microglia results in paracrine activation of astrocytes. This activation in turn is predicted to enhance production of toxic mediators by astrocytes that include NO and ROS. These factors are suggested to act additively or synergistically with neurotoxic factors produced by microglia (Fig. 7A). Experiments using mixed neuronal cultures are of particular interest in this regard because they suggest that activated microglia and astrocytes produce factors that exhibit relative specificity for TH+ neurons (Fig. 2H and I). Conversely, distinct neuronal cell types might exhibit different sensitivities to neurotoxic factors based on protective systems, such as those conferred by genes under the control of the PGC1α coactivitor (St-Pierre et al., 2006). Defining the specific identities of the pathologically important factors produced by microglia and astrocytes and their relative ability to exert toxic effects on different types of neurons will be important future goals.
