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

Abstract

Background and Purpose: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 Results: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 αtubulin 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.

Ribosomal Protein S6 Hypofunction in Postmortem Human Brain Links mTORC1-Dependent Signaling and Schizophrenia

“…Our findings, together with the reduced cell area, ribosomal protein expression and rates of protein synthesis previously reported (English et al, 2015), are consistent with the reduction of the neuronal body size (Rajkowska et al, 1998;Chana et al, 2003) and of the whole-brain volume in schizophrenia (Harrison and Weinberger, 2005;Cannon et al, 2015). Dysfunctions in mTORC1/S6 pathway inhibits oligodendrocyte proliferation and maturation (Liu et al, 2014;Maas et al, 2017), contributing to an alteration in white matter integrity in schizophrenia (Flynn et al, 2003;Schoonover et al, 2019). On the other hand, the inhibition of mTORC1-dependent signaling involves a substantial reduction in the number of dendritic branches and arbor shrinkage in developing neurons (Jaworski and Sheng, 2006;Kwon et al, 2006).…”

Interactions between knockout of schizophrenia risk factor Dysbindin-1 and copper metabolism in mice

“…Previous literature has shown that decreases in copper function produce deficits in white matter integrity (Herring and Konradi, 2011). Furthermore, abnormalities in white matter diffusion, integrity, oligodendrocytes, and related white matter genes within whole brain, prefrontal cortex, and hippocampus via live imaging, genetic assay, and postmortem analysis have been repeatedly observed in SZ (Chambers and Perrone-Bizzozero, 2004;Hakak et al, 2001;Hof et al, 2002;Lyu et al, 2015;Schoonover et al, 2019), as have decreases in dysbindin (Abdolmaleky et al, 2015;Talbot, 2009;Talbot et al, 2009;Weickert et al, 2008;Weickert et al, 2004). Therefore, our finding of unaltered MBP was unexpected.…”

White Matter Integrity of the Corpus Callosum and Psychopathological Dimensions in Deficit and Non-Deficit Schizophrenia Patients

“…WM is part of the nervous tissue and mainly consists of the axonal parts of neurons and oligodendrocytes. Histopathological research has confirmed the existence of disturbances in the structure of myelin and oligodendrocytes in schizophrenia [ 20 ].…”