FAMILIAL AND DEVELOPMENTAL ABNORMALITIES OF FRONTAL-LOBE FUNCTION ANDNEUROCHEMISTRY IN SCHIZOPHRENIA

Structural abnormalities of the cerebral cortex in schizophrenia have been revealed by magnetic resonance imaging, although it is not clear whether these abnormalities are diffuse or local. We predicted that ch anges in cortical structure would result in abnormalities in biochemic al markers for the glutamate system in postmortem brain, and that the pattern of neurochemical abnormalities would be a clue to the distribu tion and extent of pathology. A number of studies have now reported in creases in biochemical and other markers of glutamatergic cell bodies and terminals in the frontal cortex in schizophrenia. These findings a re consistent with the presence of an abnormally abundant glutamatergi c innervation, which may be due to an arrest in the normal development al process of synaptic elimination. In the anterior temporal cortex an d hippocampus there is evidence of an asymmetric loss of glutamate ter minals, and of reduced GABA function, which may be secondary to the gl utamatergic deficit. Glutamate cell body markers are spared in the tem poral lobe; we argue that the loss of glutamate uptake sites may refle ct the loss of an extrinsic glutamatergic innervation of the polar tem poral cortex which arises from the frontal cortex. These fronto-tempor al projections may be vulnerable because they arise from a cytoarchite cture which has not been stabilized by remodelling during early postna tal life. There have been several therapeutic studies of drugs with ac tions on brain glutamate systems. Based on the glutamate deficiency th eories, one approach has been to enhance glutamatergic function using agonists of the N-methyl-D-aspartate-linked glycine site. However, the re are no clear therapeutic effects, and some studies report aggravati on of positive symptoms. This might be expected if, as our post-mortem studies suggested, there is excess glutamatergic innervation in some brain regions in schizophrenia. There is neuropsychological evidence t hat frontal abnormalities in schizophrenia may be genetically determin ed. We found that first degree relatives of schizophrenic patients wer e selectively impaired in tests of frontal lobe function, whereas both frontal and temporal function is impaired in patients. We concluded t hat the genetic predisposition to schizophrenia involves impaired fron tal lobe function. Psychotic symptoms develop only when a second proce ss results in a loss of fronto-temporal projections and leads to tempo ral lobe dysfunction.