Towards an Integrated Understanding of Neurotransmitter Dysfunction in Schizophrenia: A Multimodal MRI Study

PROJECT SUMMARY / ABSTRACT Schizophrenia is among the most severe and burdensome medical conditions worldwide, yet the brain alterations that lead to the symptoms of schizophrenia remain unknown. This K23 application presents a research and training program that will support the applicant on a path towards becoming an NIH-funded independent investigator focused on understanding the neurobiology of schizophrenia and related psychotic disorders. The activities in this application build on the candidate’s prior training and are set in a resource-rich environment that will foster her development of expertise in 1) application of MRS and advanced MRI neuroimaging methodologies; 2) physician-scientist approaches to studying pathophysiology in patients with schizophrenia; 3) neurocircuitry and systems neuroscience perspectives on hippocampus pathology in psychotic disorders; and 4) responsible conduct of research. The overarching goal of the research to be carried out in this application is to take findings from animal models of schizophrenia, which were motivated by original research in patients with the disorder, back to the clinical setting in order to determine whether the brain circuit alterations observed in the animal models are observable in human patients. Specifically, findings in the prenatal methylazoxymethanol acetate (MAM) rodent model, which was developed to model the alterations in dopamine function seen in patients with schizophrenia, suggest hyperactivity of the ventral (anterior) hippocampus may increase its glutamatergic output to the ventral striatum and lead, via ventral pallidal and other GABAergic projections to the ventral midbrain, to disinhibited firing of dopamine neurons. In addition, a convergence of several post mortem and in vivo imaging findings in patients suggests that abnormal GABAergic activity in the hippocampus may further compound hippocampal glutamatergic overdrive. This project will directly test the relationships among these neurochemical alterations in individual medication-free patients with schizophrenia using sophisticated magnetic resonance imaging methods. If this non-invasive, multimodal imaging paradigm provides evidence to relate hippocampal GABA and glutamate abnormalities to dopamine system dysfunction in patients with schizophrenia, it would have important implications for the understanding of the brain bases of schizophrenia, and would generate a novel multimodal imaging paradigm for testing new molecular, anatomical, and circuit-modulating targets for treatment of this devastating illness.