Alterations in GABA-related Transcripts in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia
Harvey M. Morris, Ph.D.
University of Pittsburgh, 2009
Besides the financial burden upon society, families undergo a substantial emotional burden when presented with a loved one affected by schizohprenia. Elucidation of the pathophysiology underlying the core features of schizophrenia is necessary for the development of more effective treatment targets. Cognitive deficits are regarded as a core feature of schizophrenia and are thought to arise from alterations in ã-aminobutyric acid (GABA)-containing interneurons in the dorsolateral prefrontal cortex (DLPFC). Specifically, postmortem studies have demonstrated decreased levels of the mRNA encoding the 67 kDa isoform of glutamic acid decarboxylase (GAD67), an enzyme that synthesizes GABA, and this alteration seems to be specific to certain subsets of GABA neurons. For example, parvalbumin and somatostatin mRNAs, which are expressed in separate subsets of GABA neurons, were decreased, whereas calretinin mRNA, expressed in a third subset of GABA neurons, was unchanged in schizophrenia. The studies in this thesis examined the compartmental and cellular expression of and the potential causal mechanisms of reductions in SST mRNA expression; furthermore, the disease and cellular specificity of and post-synaptic consequences of reductions in SST mRNA expression were examined. We found that reductions in the levels of SST mRNA appear to be restricted to SST interneurons that do not contain NPY mRNA in the gray matter and are due to reductions in expression per neuron. These alterations appear to be a consequence of impaired neurotrophin signaling through the trkB receptor. Also, the profile of alterations in GABA-related mRNA expression is specific to schizophrenia. Finally, a post-synaptic receptor of SST, SST receptor subtype 2 (SSTR2), mRNA is reduced in schizophrenia. Since the SST protein is putatively inhibitory and SST-containing interneurons target the distal dendrites of pyramidal neurons, these data suggest reduced inhibition of pyramidal neurons and may represent a compensatory mechanism to increase excitatory drive. We conclude that reductions in SST and SSTR2 mRNA represent a downstream consequence of a neuropathological entity in the DLPFC of individuals with schizophrenia and contribute to cognitive dysfunction in schizophrenia.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-06242009-105648 |
| Date | 30 September 2009 |
| Creators | Morris, Harvey |
| Contributors | Robert Sweet, M.D., David A. Lewis, M.D., Marc Sommer, Ph.D., Etienne Sibille, Ph.D., Sacha Nelson, M.D., Ph.D., Susan Sesack, Ph.D. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-06242009-105648/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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