A 2-PROCESS THEORY OF SCHIZOPHRENIA - EVIDENCE FROM STUDIES IN POSTMORTEM BRAIN

Glutamate and GABA are the principle neurotransmitters of the cerebral cortex and are known to modulate dopaminergic function. Evidence of s tructural abnormalities in the cortex raises the possibility that schi zophrenia involves disturbances of cortical amino-acid neurotransmissi on. The psychotomimetic effects of phencyclidine, a glutamate antagoni st, have been taken to suggest that schizophrenia involves reduced bra in glutamate function. Direct evidence for diminished glutamate functi on in schizophrenia is lacking. However, in polar temporal cortex and hippocampus we reported evidence of an asymmetric loss of glutamate te rminals, and of reduced GABA function, which may be secondary to the l oss of glutamatergic input. Glutamate cell body markers are spared in temporal lobe; the neurones which degenerate may originate in frontal cortex. A number of studies have reported increases in markers of glut amatergic cell bodies and terminals in orbital frontal cortex in schiz ophrenia. These findings are consistent with the presence of an abnorm ally abundant glutamatergic innervation, which may be the result of an arrest in the normal process of cellular and synaptic elimination whi ch occurs during development. There is evidence that frontal abnormali ties in schizophrenia are genetically determined. We suggest that glut amatergic abnormalities in anterior temporal cortex in schizophrenia a re the result of the degeneration of fronto-temporal projections. Orbi tal frontal projections to polar temporal cortex may be prone to degen eration because they arise from an unstable frontal cortical cytoarchi tecture which has not completed the normal process of post-natal remod elling. The structural abnormality of the orbital frontal region may c onfer vulnerability to some intrinsic or extrinsic mechanism, which br ings about a progressive degeneration of projections to polar temporal lobe. (C) 1997 Elsevier Science Ltd.