Schizophrenia is increasingly coming to be seen as a disorder of neuronal connectivity, which may be impaired at several levels. Abnormalities in both presynaptic machinery and dendritic spines of the cerebral cortex are clearly implicated by autopsy studies. The evidence for abnormalities of the white matter comes largely from magnetic resonance imaging studies, which fairly consistently demonstrate decreased fractional anisotropy (FA) in cerebral white matter, as well as correlations between FA deficits and functional deficits in schizophrenia. The anatomical and biochemical substrates of these abnormalities are unknown and can only be determined by autopsy studies, which so far have focused little attention on white matter. Autopsy studies have, however, demonstrated diminished expression of myelin-related genes in grey matter, with varying degrees of evidence that these decreases are related to polymorphisms, possibly linked to schizophrenia, of genes that regulate myelination. Initial results from our laboratory with routine histochemical stains for myelin in prefrontal white matter demonstrate no difference between elderly schizophrenia and nonpsychiatric subjects but show a significant correlation between myelin integrity and cognitive function at the onset of schizophrenia and in the final years of life. We have also found evidence of decreased expression of mRNA for several myelin-related genes in the right anterior cingulum, a structure frequently demonstrating decreased FA in schizophrenia. In the same region, we find a mildly decreased level of myelin basic protein. We now propose the first large, multifaceted autopsy study to focus on white matter in schizophrenia. We will compare ventral and dorsal left prefrontal white matter and will supplement routine myelin staining with more sensitive and targeted examinations in a series of optimally collected, young (mean age -50) cases with thorough clinical, neuropathological, and toxicological characterization, including retrospective assessments of cognitive impairment at the onset and end of schizophrenia. We will employ: (1) systematic semiquantitative assessment of routine myelin stains and immunohistochemical stains for specific protein components of white matter, (2) biochemical quantitation of these components and their respective mRNA, (3) stereological determination of axon length density and the distributions of axon diameter and myelin sheath thickness;and (4) histological evaluation of microglial activation, a sensitive indicator of white matter damage.