The Modulation of Neuronal Excitotoxicity by Astrocytes

The important role of glutamate as the mediator of neuronal cell death by receptor-mediated mechanisms that involve the accumulation of cytosolic calcium was established primarily in the 1980's by work in several laboratories, including those of Drs. Stuart Lipton and Paul Rosenberg in this IDDRC. In 1989, Rosenberg demonstrated the crucial role of astrocytes in the modulation of neuronal vulnerability to glutamate. Thus Rosenberg demonstrated a 100-fold increase in neuronal vulnerability to glutamate when neurons were grown in culture in the absence of astrocytes (Neurosci. Lett., 1989). Rosenberg was able to define the intrinsic vulnerability of neurons to glutamate and demonstrate that the effective toxic concentration, i.e., approximately 5 MM, is significantly lower than previously documented by a large number of studies of glutamate toxicity using conventional astrocyte-rich cultures. The protection afforded by astrocytes was shown to be due to their avid glutamate uptake transport systems. These observations were important because they suggested that disturbances in glutamate transport by astrocytes could accentuate neuronal excitotoxicity under various circumstances. Subsequent research by Dr. Rosenberg has provided substantial support for this hypothesis.