All ETDs from UAB

Advisory Committee Chair

Miguel Melendez-Ferro

Advisory Committee Members

Edwin W Cook Iii

Linda Overstreet-Wadiche

Franklin Amthor

Rosalinda C Roberts

Diane Tucker

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Dopaminergic neurotransmission anomalies are a well-established aspect of schizophrenia, a devastating mental disorder that affects approximately 1% of the world population. The substantia nigra/ventral tegmental area (SN/VTA), which extends from diencephalic to mesencephalic territories, provides the largest dopaminergic input to the brain. The SN/VTA contains subpopulations of dopaminergic neurons that project preferentially through different pathways, providing dopamine input to brain regions where dopaminergic anomalies have been reported in schizophrenia. We hypothesized that anomalies in the synthesis of tyrosine hydroxylase (TH), the rate-limiting enzyme for the production of dopamine, could contribute to the dopaminergic anomalies observed in this disorder. We first tested the expression of TH mRNA and protein in schizophrenia and matched control cases. In our schizophrenia cases we found significant deficits in TH protein expression that were driven by the rostral SN/VTA, which preferentially provides dopaminergic input to cortical areas. Next, we assessed if metabolic anomalies in the SN/VTA could contribute to this deficit by examining cytochrome c oxidase (COX) activity and subunit composition. We found a decrease in specific key subunits for the assembly and function of the enzyme. Interestingly, these deficits were not accompanied by alterations in COX activity. These findings can be explained by the fact that measurements of COX activity in postmortem tissue provided only a "snapshot" of the basal activity at time of death, while changes in subunit protein expression are related to long-term regulation of the enzyme, affecting the "reserve capacity" of the mitochondria to respond to higher energy demands. Finally, we performed neuronal counts of dopaminergic and total number of neurons, as well as a qualitative analysis of TH expression in the SN/VTA of schizophrenia and matched controls using immunohistochemistry. We found that, while neuronal counts were unaltered, TH protein expression was markedly reduced within rostral areas of the SN/VTA in schizophrenia. These studies support that presynaptic dopaminergic deficits are concentrated in cell populations that preferentially project through the mesolimbic and mesocortical pathways. Thus, our results indicate that presynaptic dopaminergic anomalies contribute to the hypodopaminergia of schizophrenia neuropathology, which is directly related to the negative symptomology and cognitive impairments of this disorder.

Share

COinS