THE PAST 2 decades have witnessed a resurgence of interest in identifying the structural underpinnings of schizophrenia. Neuroimaging studies have shown that in schizophrenic subjects the brain as a whole and the frontal cortex in particular are smaller than in normal subjects.1- 3 A wealth of data has established that prefrontal cortical dysfunction—for example, impairments in working memory, abstract thinking, attention, and language coherency—are prominent symptoms of schizophrenia.4 Yet just what is missing in the schizophrenic prefrontal cortex to account for these deficits has been hard to pinpoint. There are no obvious signs of pathology, neuronal loss, or gliosis in the prefrontal cortex in schizophrenic patients. Perhaps because of the subtle nature of the structural deficit, progress in identifying an anatomical substrate for schizophrenia has come only with the application of quantitative methods. Recent stereologic analyses of the prefrontal cortex have begun to home in on the deficit, revealing the presence of increased neuronal density in schizophrenic patients.5,6 The implication of this finding is that the interneuronal space, rather than the neurons themselves, is underrepresented in the prefrontal cortex. Although appearing empty in Nissl preparations, this space is actually chock-full of presynaptic and postsynaptic neuronal processes. Thus, the predominant pathology in schizophrenia is not the classic form involving neuronal cell death, but instead a sublethal reduction in the elements of neuronal connectivity, the reduced neuropil deficit.7 Now the challenge has moved to determining what components in this composite neuropil compartment are impoverished.
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