Basing primarily on the facts of altered levels of glutamate neurotransmitter, its receptors and transporters in schizophrenic brain, the "glutamatergic hypothesis" of schizophrenia has been broadened into the field of brain glutamate metabolism. Significantly changed levels of glutamine synthetase (GS) and glutamate dehydrogenase (GDH), the key enzymes involved in glutamine-glutamate cycling between neurons and glia, have been found in the prefrontal cortex (area 10) of patients with schizophrenia compared to controls (P<.01). The data were obtained by enzymatic activity determinations as well as immunoreactivity level evaluations for GS, glutamine synthetase-like protein (GSLP), and three GDH isoenzymes in brain extracts by immunoblotting using specific polyclonal and monoclonal antibodies. Inverse changes in amounts of proteins of GS and GSLP, as well as elevation in amounts of GDH isoenzymes have been observed in schizophrenia. The presented results provide evidence for the impairment of glutamate metabolism and, in turn, abnormalities in functioning of the glutamate-glutamine cycle in the frontal cortex of patients with schizophrenia.