LEVELS OF THE GROWTH-ASSOCIATED PROTEIN GAP-43 ARE SELECTIVELY INCREASED IN ASSOCIATION CORTICES IN SCHIZOPHRENIA

The pathophysiology of schizophrenia may involve perturbations of syna ptic organization during development, The presence of cytoarchitectura l abnormalities that may reflect such perturbations in the brains of p atients with this disorder has been well-documented. Yet the mechanist ic basis for these features of the disorder is still unknown, We hypot hesized that altered regulation of the neuronal growth-associated prot ein GAP-43, a membrane phosphoprotein found at high levels in the deve loping brain, may play a role in the alterations in brain structure an d function observed in schizophrenia, In the mature human brain, GAP-4 3 remains enriched primarily in association cortices and in the hippoc ampus, and it has been suggested that this protein marks circuits invo lved in the acquisition, processing, and/or storage of new information , Because these processes are known to be altered in schizophrenia, we proposed that GAP-43 levels might be altered in this disorder, Quanti tative immunoblots revealed that the expression of GAP-43 is increased preferentially in the visual association and frontal cortices of schi zophrenic patients, and that these changes are not present in other ne uropsychiatric conditions requiring similar treatments. Examination of the levels of additional markers in the brain revealed that the level s of the synaptic vesicle protein syaptophysin are reduced in the same areas, but that the abundance of the astrocytic marker of neurodegene ration, the glial fibrillary acidic protein, is unchanged, In situ hyb ridization histochemistry was used to show that the laminar pattern of GAP-43 expression appears unaltered in schizophrenia, We propose that schizophrenia is associated with a perturbed organization of synaptic connections in distinct cortical associative areas of the human brain , and that increased levels of GAP-43 are one manifestation of this dy sfunctional organization.