All ETDs from UAB

Advisory Committee Chair

James Jmw H Meador-Woodruff

Advisory Committee Members

Adrienne C Lahti

Kazutoshi Nakazawa

Vladimir Parpura

Erik Roberson

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Schizophrenia (SZ) is a complex and heterogeneous mental illness in which myriad changes across multiple neurotransmitter systems (dopamine, serotonin, GABA, glutamate, and others) have been reported. Numerous regulatory mechanisms have been explored in SZ research and rather than being a disorder of one specific neurotransmitter pathway, SZ may instead be a disturbance of intracellular signaling processes that underlie the regulation of these systems. The AKT-mTOR signaling cascade plays an important role in core cellular processes of cell growth, metabolism and survival and is one such potential candidate. Abnormalities in AKT expression and activity have been consistently implicated in SZ pathophysiology through gene association studies, postmortem brain evidence and animal studies. However, there is a lack of direct evidence to support the hypothesis of deficits in mTOR complex expression, activity and downstream effector functions. Therefore, I hypothesized that down-regulation of the AKT-mTOR signaling pathway in the dorsolateral prefrontal cortex (DLPFC) contributes to SZ pathophysiology through dysregulation of mTOR complex formation and downstream effector functions. This thesis sought to characterize abnormalities in expression, phosphorylation and kinase activity of AKT-mTOR signaling proteins in SZ DLPFC. I observed reduced expression and/or phosphorylation of the key signaling proteins, AKT, mTOR and GßL, as well as mTOR complexes in SZ brain. Additionally, I found aberrant activation of S6RP and PKCα, proteins downstream of mTOR complexes in this signaling pathway. Using kinome arrays, I demonstrated that SZ subjects have a distinct kinase activity profile when compared to non-psychiatrically ill subjects for both males and females. I also observed that samples from SZ postmortem brains are globally more sensitive to rapamycin-induced mTOR inhibition, and that AMPK is the most important kinase contributing to these differences. Although further work will be required to determine the consequences of disrupted mTOR signaling in SZ, these findings demonstrate molecular alterations in upstream activators, downstream substrates, kinase activity and mTOR complex components directly in SZ postmortem brain and suggest that dysregulation of this signaling cascade may contribute to cognitive deficits in SZ patients.

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