All ETDs from UAB

Advisory Committee Chair

Rosalinda C Roberts

Advisory Committee Members

Adrienne Lahti

Lori L McMahon

Thomas Norton

Scott Wilson

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Schizophrenia is a mental illness affecting 1% of the population worldwide. Treatment options are limited for patients, due in part to the lack of understanding of the pathophysiological mechanisms of schizophrenia. In order to improve treatment, it is vital to gain a better understanding of the underlying pathology of the disorder. One region of particular interest is the nucleus accumbens (NAcc). Part of the ventral striatum, this region is thought to play a role in schizophrenia pathology for multiple reasons: afferent input of many brain regions implicated in schizophrenia is integrated here; the dopamine and glutamate systems, both known to be disrupted in schizophrenia, are highly interactive in the NAcc; and animal models with disruptions in the NAcc suggest abnormalities in this region could lead to symptoms of schizophrenia. Despite these reasons, there is little evidence from human studies to support the role of the NAcc in the pathology of schizophrenia. Ultrastructural studies in the NAcc of postmortem human tissue analyzed synaptic density in schizophrenia and control subjects. There was an increase in the density of asymmetric axospinous synapses, characteristic of excitatory input, in the NAcc of schizophrenia subjects. Consistent with this finding, a western blot analysis measuring protein levels of the vesicular glutamate transporter found increased levels of vGLUT2 which is localized in glutamatergic axon terminals. These findings suggest the NAcc receives elevated excitatory input in schizophrenia. The NAcc receives dense dopaminergic projections and elevated striatal dopamine is a hallmark characteristic of schizophrenia. Within the NAcc however, the ultrastructrual analysis found no difference in symmetric synapses in schizophrenia, the type formed by dopaminergic input. Further, no difference was found in protein levels or staining density of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. These results suggest that the NAcc has normal levels of dopamine synthesis in schizophrenia. These findings suggest the NAcc receives excessive glutamatergic input to the region. These studies provide the first ultrastructural evidence in human tissue to support the role of the NAcc in schizophrenia, and are highly consistent with hypotheses regarding the role of the NAcc in the pathophysiology of the disorder.

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