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Cortical Glutamic Acid Decarboxylase 67 Expression in Schizophrenia: Defining the Deficit

Curley, Allison Ashley (2011) Cortical Glutamic Acid Decarboxylase 67 Expression in Schizophrenia: Defining the Deficit. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

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.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Curley, Allison Ashleyaac31@pitt.eduAAC31
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSesack, Susansesack@pitt.eduSESACK
Committee MemberLewis, Davidlewisda@upmc.eduTNPLEWIS
Committee MemberFanselow, Erikacircuit@pitt.eduCIRCUIT
Committee MemberFish, Kennethkenfish@mac.com
Committee MemberAkbarian, SchahramSchahram.Akbarian@umassmed.edu
Committee MemberHastings, Teresahastings@bns.pitt.eduTHASTING
Date: 16 September 2011
Date Type: Completion
Defense Date: 5 August 2011
Approval Date: 16 September 2011
Submission Date: 12 August 2011
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: GAD67; gamma oscillations; GAT1; parvalbumin; prefrontal cortex
Other ID: http://etd.library.pitt.edu/ETD/available/etd-08122011-115810/, etd-08122011-115810
Date Deposited: 10 Nov 2011 19:59
Last Modified: 19 Dec 2016 14:37
URI: http://d-scholarship.pitt.edu/id/eprint/9072

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