One of the most consistent and replicated postmortem findings in schizophrenia is the reduced expression ofthe mRNA encoding the 67 kD isoform of glutamic acid decarboxylase (GAD67), the enzyme principallyresponsible for the synthesis of GABA. A central hypothesis of the Center is that disturbances in GABAneurotransmission play a key role in the information processing impairments observed in schizophrenia.These impairments represent a prominent and disabling feature of schizophrenia and a strong predictor offunctional outcome. Thus, understanding the pathophysiologic mechanisms underlying cognitiveimpairments has become a critical focus in the development of novel therapeutics for the illness. However, todate, there is no direct, in vivo evidence that GABA function is altered in schizophrenia or that the GABAabnormalities observed in postmortem studies are linked to functional impairments in this illness.Consequently, the goal of this project is to develop and validate a methodology for exploring, in vivo, theevidence that GABA transmission is broadly impaired, across cortical brain regions, in subjects withschizophrenia. This project will (1) validate the use of [11C]flumazenil PET to detect changes in extracellularGABA levels resulting from the administration of tiagabine (a drug which inhibits the reuptake of GABA byblocking the GABA transporter, GAT1) and (2) examine tiagabine-induced changes in GABA levels incortical regions in first-episode, antipsychotic-naTve, schizophrenia subjects (FEAN-S) compared withhealthy controls. We predict that schizophrenia will be associated with a deficit in the ability to increaseextracellular GABA levels in response to tiagabine when measured in vivo, using PET. All subjects willparticipate in Project 4-Phillips which will create a multi-modal dataset permitting us to explore the existenceof a number of relationships predicted by the overall model of this Center. We will test the hypothesis that, inFEAN-S subjects, deficits in the ability to increase GABA levels, as indicated by blunting of the change in[11C]flumazenil binding in response to tiagabine, will be associated with impaired gamma oscillatory activityas measured by EEC, and decreased fMRI BOLD signal, during a cognitive control task, and that the level ofcognitive impairment will be inversely correlated with the ability to increase GABA levels. This project willprovide a key link between the postmortem studies of Project 1-Lewis and the clinical studies outlined inProject 4-Phillips. It will allow us to directly test the hypothesis that GABA transmission is reduced inschizophrenia (Project 1-Lewis) and, in combination with data from Project 4-Phillips, determine if reducedGABA is associated with the oscillation and fMRI disturbances observed in vivo. The methods developedthrough this project will thus provide a innovative biomarker that can be used to monitor the effects of noveltherapeutic drugs in schizophrenia.
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