All ETDs from UAB

Advisory Committee Chair

Robert E McCullumsmith

Advisory Committee Members

James H Meador-Woodruff

J David Sweatt

Anne Theibert

Rita Cowell

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

INTRACELLULAR SIGNALING AND INTEGRATION ABNORMALITIES IN SCHIZOPHRENIA Adam J. Funk DEPARTMENT OF NEUROBIOLOGY ABSTRACT The pathophysiology of schizophrenia is complex and diverse, with many classes of receptors, neurotransmitters, and brain regions implicated in this illness. The many hypotheses proposed have yet to fully explain the heterogeneity of the genetic, postmor-tem, and clinical evidence. It is the goal of this dissertation to integrate the current hy-potheses of schizophrenia into a unified hypothesis of abnormal intracellular signaling and signal integration. Inconsistencies in genetic and postmortem findings suggest that the development of schizophrenia is multifaceted, and the heterogeneity of symptoms supports the hypothesis of any number of intracellular signaling abnormalities as the pre-cipitating factor in the development of this devastating illness. In this dissertation I ex-amined conserved intracellular signaling pathways for activation (via phosphorylation of kinases) and functional outcome (via phosphorylation of proteins with known functional consequences). Abnormal protein expression in the MAPK pathway includes decreased SynGAP, Rap2, JNK1/2, and PSD-95 in the anterior cingulate cortex (ACC). Abnormal activation, determined by phosphorylation, of the MAPK pathway includes decreased pThr183/Tyr185 JNK1/2 and pSer295 PSD-95 in the ACC in schizophrenia. Abnormal protein expression in the cAMP pathway includes increased RACK1, Fyn, and Cdk5 in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia. Abnormal function, deter-mined by phosphorylation, of the cAMP pathway includes increased pTyr1336 NR2B and pSer295 PSD-95 in the DLPFC in schizophrenia. Signaling through G protein-coupled receptors (GPCRs) is regulated by G protein-coupled receptor kinases (GRKs). I measured the protein and mRNA expression of GRKs 2-6 in the anterior cingulate cortex. I found increased transcript expression for GRK2 and GRK5, and increased protein ex-pression for GRK5. The abnormalities in GPCR regulation, coupled with alterations of signaling cascades downstream of these proteins suggest that dysfunction of intracellular signaling and signal integration contribute to the pathophysiology of schizophrenia.

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