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Alterations in GABA-related Transcripts in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia

Morris, Harvey (2009) Alterations in GABA-related Transcripts in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Alterations in GABA-related Transcripts in the Dorsolateral Prefrontal Cortex of Subjects with SchizophreniaHarvey M. Morris, Ph.D.University of Pittsburgh, 2009Besides 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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSibille,
Committee MemberLewis, David A.lewisda@upmc.eduTNPLEWIS
Committee MemberSommer,
Committee MemberSweet, Robertsweetra@upmc.eduSWEET
Committee MemberNelson,
Committee MemberSesack, Susansesack@pitt.eduSESACK
Date: 30 September 2009
Date Type: Completion
Defense Date: 27 May 2009
Approval Date: 30 September 2009
Submission Date: 24 June 2009
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Neuroscience
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: major depressive disorder; npy; receptors; schizoaffective disorder; bipolar disorder; somatostatin
Other ID:, etd-06242009-105648
Date Deposited: 10 Nov 2011 19:48
Last Modified: 19 Dec 2016 14:36


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