Pathology of white matter integrity in three major white matter fasciculi: A post-mortem study of schizophrenia and treatment status

Imaging studies have shown that people with schizophrenia exhibit abnormal connectivity termed "dysconnectivity" in several white matter tracts, including the cingulum bundle (CB), corpus callosum (CC), and arcuate fasciculus (AF). This study aimed to elucidate potential contributors to schizophrenia "dysconnectivity." Experimental approach: Western blot analysis was used to compare protein levels of myelin basic protein, neurofilament heavy, autophagosome marker LC3, and microtubule marker α-tubulin in post-mortem human CB, CC, and AF in schizophrenia subjects (SZ) and matched normal controls (NC). Additionally, SZ cases were subdivided by treatment status: off-medication (OFF) or on-medication (ON). Key

Imaging studies have shown that people with schizophrenia exhibit abnormal connectivity termed "dysconnectivity" in several white matter tracts, including the cingulum bundle (CB), corpus callosum (CC), and arcuate fasciculus (AF). This study aimed to elucidate potential contributors to schizophrenia "dysconnectivity." Experimental approach: Western blot analysis was used to compare protein levels of myelin basic protein, neurofilament heavy, autophagosome marker LC3, and microtubule marker α-tubulin in post-mortem human CB, CC, and AF in schizophrenia subjects (SZ) and matched normal controls (NC). Additionally, SZ cases were subdivided by treatment status: off-medication (OFF) or on-medication (ON). Key

In the CC, the combined SZ group exhibited less neurofilament heavy protein than the NCs. In the CB, the combined SZ group had similar levels of α-tubulin protein versus NC, but OFF subjects had increased α-tubulin protein versus ON and NCs. There were significant correlations between α-tubulin and all other proteins but only in the CB. The strong negative relationship between α-tubulin versus myelin basic protein and α-tubulin versus LC3 in NCs was absent in SZs; coefficients comparison showed significant differences. Preliminary race analyses revealed that African American SZ had less AF α-tubulin than Caucasian SZ and African American normal controls. Conclusions and implications: The results show a relationship between tract- and protein-specific abnormalities and diagnosis, treatment, and race. These data suggest there is a dysregulation of the relationship between α-tubulin and the other markers of white matter integrity observed in the CB in schizophrenia.