Cognitive impairments are a core feature of schizophrenia and the best predictor of functional outcome, though current pharmacotherapies offer only limited cognitive improvement. Cognitive deficits span multiple domains and thus may reflect an overarching alteration in cognitive control, the ability to adjust thoughts or behaviors to achieve goals. Cognitive control depends on the dorsolateral prefrontal cortex (DLPFC), which exhibits altered activity in schizophrenia. DLPFC dysfunction is thought to be due, at least partially, to alterations in interneurons, which are regulated by levels of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD). A deficit in the 67 kDa isoform (GAD67), responsible for the majority of cortical GABA synthesis, has been widely replicated in the DLPFC of subjects with schizophrenia and is particularly prominent in the parvalbumin (PV)-containing subclass of interneurons. However, little is known about the relationship of DLPFC GAD67 mRNA levels and medication use, substance abuse, and illness severity and chronicity; translation of the transcript into protein; or protein levels in axon terminals, a key site of GABA production and function. Additionally, alterations in other GABA neurotransmission markers, including lower PV and GABA membrane transporter 1 (GAT1), are also present, and thought to result from lower GAD67 in PV neurons, though this hypothesis has not been directly tested. Accordingly, here we measured GAD67 mRNA, tissue-level protein, and axon terminal protein in PV cells, and examined whether lower PV and GAT1 mRNA are consequences of lower GAD67 protein in PV neurons. GAD67 mRNA levels were significantly 15% lower in schizophrenia subjects, but transcript levels were not associated with medication use, substance abuse, predictors or measures of disease severity, or illness chronicity. GAD67 protein levels were significantly 10% lower in total gray matter and 49% lower in PV axon terminals. These data provide an extensive characterization of the GAD67 deficit in schizophrenia, and provide novel evidence of a functional impairment in PV neurons that may underlie cognitive deficits. Additionally, PV and GAT1 mRNAs were not altered in two mouse models with lower GAD67 expression, suggesting that lower GAD67 is unlikely to be the cause of reduced PV and GAT1 mRNA in schizophrenia.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08122011-115810 |
| Date | 16 September 2011 |
| Creators | Curley, Allison Ashley |
| Contributors | Kenneth Fish, Schahram Akbarian, Erika Fanselow, David Lewis, Susan Sesack, Teresa Hastings |
| 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-08122011-115810/ |
| 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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