All ETDs from UAB

Advisory Committee Chair

Rosalinda C Roberts

Advisory Committee Members

Frank Amthor

Rita Cowell

Adrienne Lahti

Christianne Strang

Jarred Younger

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

The dystrobrevin binding protein 1 (DTNBP1) gene encodes for dysbindin-1 and is a top candidate gene for schizophrenia. Dysbindin-1 modulates copper transport crucial for myelination, monoamine metabolism, and cellular homeostasis. Schizophrenia patients (SZP) exhibit increased plasma copper, while copper-decreasing agents produce schizophrenia-like behavioral and pathological abnormalities. Therefore, we sought to investigate the relationship between dysbindin-1 and copper in postmortem SZP substantia nigra (SN) and hippocampus. Additionally, we analyzed the role of quetiapine treatment and cognitive function in dysbindin-1 knockout (sdy) mice and their wild-type (WT) littermates. Western blot assessment of SN revealed protein domain alterations of copper transporters ATP7A and CTR1 in SZP. Decreased transmembrane CTR1 and dysbindin 1B/C were seen, but elevated C-terminus ATP7A (driven by medicated SZP) was also observed. Unmedicated SZP exhibited less N-terminus ATP7A protein than controls and medicated SZP, suggesting medication-induced rescue. SZP exhibited less SN copper content than controls. The hippocampus proper, dentate gyrus (DG), entorhinal cortex (EC), and subiculum were richly immunolabeled for CTR1 in controls and SZP as shown by light microscopy. Qualitatively, CTR1 immunolabeling was present in the same cell types in both groups. In the superficial area of the EC, neuropil and cells showed lower optical density values in SZP versus controls. The opposite pattern was observed in the DG molecular layer- SZP had significantly higher optical density values than controls. qRT-PCR revealed that after treatment, WTs exhibited elevated cortical transthyretin (TTR). Hippocampal CTR1, TTR, and MBP mRNA were decreased by quetiapine regardless of genotype. Sdy mice exhibited excess peripheral copper. Both hindlimb clasping severity and ledge instability were exacerbated in untreated sdy vs WT mice. Interestingly, only ledge instability was rescued with quetiapine treatment. These results provide the first evidence of disrupted copper transport in schizophrenia. Furthermore, these alterations appear to result in a copper-deficient state. These findings suggest altered copper transport in SZP does not require decreased dysbindin-1, but that it is sufficient. Furthermore, quetiapine alters genetic expression but not behavior in sdy mice, but such changes are sex and region dependent.

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