GABA deficit hypothesis of impaired visual inhibition in schizophrenia

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DESCRIPTION (provided by applicant): Cognitive deficits are now recognized as a significant source of disability in schizophrenia, which is a common, debilitating illness. Currently available treatments have, at best, modest effects on cognitive deficits. This situation calls for the elucidation of the neural mechanisms responsible for the cognitive deficits so that novel treatments can be developed. Given the complexity of schizophrenia, this goal requires first the identification of a specific impaired cognitive process so that it can be mapped onto specific underlying neural pathways and processes. These goals have proven very difficult due to the presence of generalized deficits and the complexity of some of the most notable cognitive deficits in schizophrenia. This project addresses these challenges by focusing on a relatively simple information process pathway whose functional neuroanatomy is relatively well known. We will apply the sophisticated experimental designs and methods utilized in visual psychophysics to control for generalized deficits and to identify a specific deficit in cognitive inhibition in visual processing. We will combine this approach with magnetic resonance spectroscopy to test the hypothesis of an association between GABA deficiency and cognitive inhibition of visual processing in schizophrenia. The successful completion of this project will represent the first in a series of studies that will eventually lead to one of the first demonstrations of a neural mechanism of an impaired cognitive process in schizophrenia. This work promises to yield potential disease biomarkers and a micro-circuit level model of information processing deficits. This model system will facilitate future genetics, molecular and cellular studies relevant to the full understanding of the neurobiological bases of cognitive deficits in schizophrenia, and to the development of new treatments targeting them. PUBLIC HEALTH RELEVANCE: The cognitive deficits in schizophrenia represent a tremendous public health burden yet we still know very little about their neural bases. This project will study the neural mechanism of a specific information processing pathway impaired in schizophrenia by testing the hypothesis that deficiencies in GABA is associated with abnormalities in visual inhibition. This and related future studies will lead to one of the first demonstrations of a neural mechanism of cognitive deficits in schizophrenia and may lead to the identification of new biomarkers and the development of targeted therapies for cognitive deficits in schizophrenia.