Project Summary

Cameron S. Carter, M.D. (Distinguished Investigator 2007) of the M.I.N.D. Institute, has recently observed that cognitively induced synchronous activity in the gamma (40 Hz) range, associated with the engagement of cognitive control, is reduced in the dorso-lateral prefrontal cortex (DLPFC) in schizophrenia. The finding bridges the post mortem literature implicating altered DLPFC local circuit function and thalamocortical connectivity with fMRI results showing functional deficits in DLPFC associated with impaired cognition, behavioral disorganization and poor functional outcome in schizophrenia. Demonstrating that variations in continuous measures of DLPFC function are associated with specific polymorphisms of glutamic acid decarboxylase (GAD) genes would provide powerful additional evidence for the importance of GABAergic dysfunction in the DLPFC in the behavioral and cognitive deficits in schizophrenia and open up a host of new possibilities for investigating the cellular and molecular changes associated with this illness. GAD enzymes catalyze the biosynthesis of GABA in the brain and have repeatedly been shown to be decreased in the DLPFC in schizophrenia. In the proposed work, he will measure cognitively invoked PFC gamma band activity and genotype subjects (schizophrenia patients, unaffected first degree relatives and controls) to find associations between (i) variations in cognitively induced gamma band activity and increased genetic risk for schizophrenia, (ii) variations in GABA-related genotypes and risk for schizophrenia; and (iii) variations in GABA related genotypes and prefrontal induced gamma band activity. Findings should lead to a better understanding of the genetic underpinnings of the physiological disturbances in prefrontal cortical function related to impaired cognition in schizophrenia and in identifying new molecular targets for treatment development for this disabling and generally treatment refractory aspect of the illness.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS

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