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 verified that both GS mRNA and protein are localized to mature oligodendrocytes, in addition to astrocytes, and at comparable levels. In addition, we are able to detect glutamate transporter currents in recordings made from individual oligodendrocytes. However, qPCR experiments indicate that oligodendrocytes do not express any of the major glutamate transporters and thus, are likely to be using a different transporter for glutamate uptake. We have also obtained oligodendrocyte-specific GS knockout mice (cKOs) by breeding MOG-iCre animals with floxed GS animals. The cKOs do not have any gross motor deficits, and oligodendrocyte density is comparable to that of WT littermate controls. In the next six months, we will carry out experiments to elucidate the functional role of GS in oligodendrocytes.
