Show simple item record

The Role of Astrocytes in the Pathophysiology of Schizophrenia.

dc.contributor.authorSteffek, Amy E.en_US
dc.date.accessioned2007-09-05T18:52:08Z
dc.date.availableNO_RESTRICTIONen_US
dc.date.available2007-09-05T18:52:08Z
dc.date.issued2007en_US
dc.date.submitted2007en_US
dc.identifier.urihttps://hdl.handle.net/2027.42/55679
dc.description.abstractA glutamate hypothesis of schizophrenia emerged based on pharmacological evidence that N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine (PCP), can induce symptoms similar to those seen in schizophrenia. Subsequently, abnormal expression of various neuronal molecules associated with the glutamate synapse has been reported in schizophrenia. Astrocytes, a prominent glial cell in the brain, play a significant role in maintaining the structure and integrity of neural tissue and in facilitating excitatory neurotransmission, therefore, any breakdown in the structure or function of astrocytes could disrupt neuronal signaling and disturb brain function. I studied structural and functional molecules in astrocytes to determine 1) whether astrocytes are themselves globally compromised in schizophrenia, and 2) whether abnormal expression of glutamatergic molecules in astrocytes could be a contributing factor to brain dysfunction in this illness. I examined the expression of molecular markers of astrocytes as a measure of the integrity of these cells in schizophrenia. S100B, a calcium binding protein previously shown to be increased in the plasma and CSF of patients with schizophrenia, was not altered. I found that the intermediate-filament glial fibrillary acidic protein (GFAP), a component of the astrocyte cytoskeleton, was significantly altered in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in schizophrenia. I also measured the expression of two astrocytic enzymes involved in glutamate function: glutamine synthetase, involved in recycling synaptic glutamate, and serine racemase, which synthesizes the NMDA receptor co-agonist D-serine. Glutamine synthetase was significantly decreased in the superior temporal gyrus and ACC, and protein expression of serine racemase was increased in the hippocampus in schizophrenia. This was the first study to demonstrate altered expression of glutamine synthetase in these brain regions, and the first report of serine racemase expression abnormalities in schizophrenia. These findings suggest that astrocytes contribute to the pathophysiology of schizophrenia and that astrocytic molecules involved in cytoskeletal integrity and glutamatergic function are compromised in this illness. Schizophrenia is a complex illness that requires a reappraisal of the existing neuronal model to include an astrocytic hypothesis of dysfunction, which could lead to a better understanding of schizophrenia, and provide novel treatment strategies in this illness.en_US
dc.format.extent26 bytes
dc.format.extent2459058 bytes
dc.format.mimetypetext/plain
dc.format.mimetypeapplication/pdf
dc.language.isoen_USen_US
dc.subjectGlutamateen_US
dc.subjectPostmortemen_US
dc.subjectGliaen_US
dc.titleThe Role of Astrocytes in the Pathophysiology of Schizophrenia.en_US
dc.typeThesisen_US
dc.description.thesisdegreenamePhDen_US
dc.description.thesisdegreedisciplineNeuroscienceen_US
dc.description.thesisdegreegrantorUniversity of Michigan, Horace H. Rackham School of Graduate Studiesen_US
dc.contributor.committeememberFisher, Stephen K.en_US
dc.contributor.committeememberMeador-Woodruff, James H.en_US
dc.contributor.committeememberDalack, Gregory W.en_US
dc.contributor.committeememberFrey, Kirk A.en_US
dc.contributor.committeememberLopez, Juan F.en_US
dc.subject.hlbsecondlevelNeurosciencesen_US
dc.subject.hlbtoplevelHealth Sciencesen_US
dc.contributor.affiliationumcampusAnn Arboren_US
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/55679/2/asteffek_1.pdf
dc.owningcollnameDissertations and Theses (Ph.D. and Master's)


Files in this item

Show simple item record

Remediation of Harmful Language

The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.

Accessibility

If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.