Glutamine synthetase (GS) is an enzyme that converts glutamate and ammonia into glutamine. It is thought to be essential for regulating levels of glutamate and ammonia in the brain, and changes in GS expression and enzymatic activity have been reported in several neurological disorders, including epilepsy, hepatic encephalopathy, and Alzheimers disease. GS is commonly described as being exclusively expressed in astrocytes, which take up glutamate from the extracellular space, and is widely used as an astrocyte-specific cell type marker. Unexpectedly, we observed widespread GS expression in mature oligodendrocytes throughout the brain. Given the potential implications of this finding on our current understanding of the brain glutamate-glutamine cycle, brain ammonia processing, and oligodendrocyte function, we decided to investigate the role of GS in oligodendrocytes. In the past year, we have characterized mice in which oligodendrocyte GS has been conditionally deleted (cKOs). cKOs show profound reductions in the levels of brain glutamate and glutamine, as well as deficits in glutamatergic neuronal tranmission in the midbrain. In addition, cKOs are impaired in cocaine sensitization, a behavior that is known to require glutamate signaling in the midbrain. Therefore, we conclude that oligodendrocyte GS is required for maintaining glutamate synaptic transmission in the brain.
