Project 5: In vivo measurement of GABA transmission in healthy controls & subject

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One of the most consistent and replicated postmortem findings in schizophrenia is the reduced expression of the mRNA encoding the 67 kD isoform of glutamic acid decarboxylase (GAD67), the enzyme principally responsible for the synthesis of GABA. A central hypothesis of the Center is that disturbances in GABA neurotransmission 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 of functional outcome. Thus, understanding the pathophysiologic mechanisms underlying cognitive impairments has become a critical focus in the development of novel therapeutics for the illness. However, to date, there is no direct, in vivo evidence that GABA function is altered in schizophrenia or that the GABA abnormalities 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, the evidence that GABA transmission is broadly impaired, across cortical brain regions, in subjects with schizophrenia. This project will (1) validate the use of [11C]flumazenil PET to detect changes in extracellular GABA levels resulting from the administration of tiagabine (a drug which inhibits the reuptake of GABA by blocking the GABA transporter, GAT1) and (2) examine tiagabine-induced changes in GABA levels in cortical regions in first-episode, antipsychotic-naTve, schizophrenia subjects (FEAN-S) compared with healthy controls. We predict that schizophrenia will be associated with a deficit in the ability to increase extracellular GABA levels in response to tiagabine when measured in vivo, using PET. All subjects will participate in Project 4-Phillips which will create a multi-modal dataset permitting us to explore the existence of a number of relationships predicted by the overall model of this Center. We will test the hypothesis that, in FEAN-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 activity as measured by EEC, and decreased fMRI BOLD signal, during a cognitive control task, and that the level of cognitive impairment will be inversely correlated with the ability to increase GABA levels. This project will provide a key link between the postmortem studies of Project 1-Lewis and the clinical studies outlined in Project 4-Phillips. It will allow us to directly test the hypothesis that GABA transmission is reduced in schizophrenia (Project 1-Lewis) and, in combination with data from Project 4-Phillips, determine if reduced GABA is associated with the oscillation and fMRI disturbances observed in vivo. The methods developed through this project will thus provide a innovative biomarker that can be used to monitor the effects of novel therapeutic drugs in schizophrenia.