Glutamine synthetase (GS) content was investigated using immunohistochemical methods in the hippocampus, cerebellum and spinal cord of rats after long-term portocaval anastomosis (PCA). Six months after surgery, GS content was increased in several areas of each region and decreased in others, compared with controls. In the hippocampus, the CA1-CA3 pyramidal subfields and the dentate molecular layer had a high level of GS expression; PCA reduced GS content in other hippocampal regions, such as the dentate hilus. In the cerebellum, PCA significantly increased GS immunoreactivity in the Bergmann glial processes of the molecular layer and decreased GS immunoreactivity in astrocytes of the granule cell layer. In the spinal cord, GS immunoreactivity increased in the dorsal horn and decreased in the ventral horn. Blood vessels located in zones with GS-immunopositive perineuronal astrocytes in PCA-exposed brains were surrounded by strongly GS-immunostained perivascular processes. These results suggest that PCA exposure had a differential effect on GS expression in different regions of the central nervous system. The increased immunoreactivity of GS-positive cells in PCA-exposed brains correlates with glutamatergic areas, which may contribute to protecting neurons against extracellular glutamate and/or ammonia excess.