All ETDs from UAB

Advisory Committee Chair

Robert E McCullumsmith

Advisory Committee Members

James Meador-Woodruff

Lynn Dobrunz

Robin Lester

Robin Lorenz

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The glutamate hypothesis of schizophrenia is based primarily on NMDA receptor dysfunction. Recent studies have led to an expansion of this hypothesis to include AMPA receptors which are essential for neurotransmission through NMDA receptors. Examination of total AMPA receptor protein expression in schizophrenia has been inconsistent and led to examination of AMPA receptor interacting proteins and trafficking and subcellular localization of the receptors. AMPA receptors are highly trafficked from the endoplasmic reticulum to the synapse and in a complex system of endosomes. Alterations in the subcellular localization of these receptors may be a part of the underlying pathophysiology of schizophrenia. I measured expression of multiple proteins that interact with AMPA receptors in postmortem dorsolateral prefrontal cortex tissue from patients with schizophrenia. I developed immunoisolation techniques to isolate two endosomal compartments and used a modified centrifugation protocol to isolate the endoplasmic reticulum from these samples as well. Following western blot and electron microscopic verification of subcellular fraction isolation and enrichment, I measured the protein expression of the AMPA receptor subunits. I found increased expression of two proteins involved in forward trafficking of AMPA receptors, SAP97 and GRIP1, in schizophrenia. In the isolated early endosomes, I found increased expression of the AMPA receptor subunit GluR1. Taken together, these findings implicate altered forward trafficking of AMPA receptors in schizophrenia. However, the lack of significant changes in multiple other proteins, as well as lack of changes in protein expression in any of the AMPA receptor subunits in the late endosomes or endoplasmic reticulum diminishes the likelihood that altered AMPA receptor trafficking and subcellular localization is a prominent feature in the underlying pathophysiology. We must consider that with the exception of a change in one AMPA receptor subunit in one subcellular fraction, AMPA receptor trafficking may be largely intact in schizophrenia.

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