Mechanisms underlying astroglial influence on neuronal function in schizophrenia

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Abstract/Project Summary Schizophrenia afflicts approximately 21 million people worldwide and 3.5 million in the United States, which translates to an exorbitant socioeconomic burden. Despite this, currently, there is no effective treatment for schizophrenia mainly attributed to its elusive pathogenesis and heterogeneous pathology. Converging evidence highlights an association of glial genes and a high susceptibility to develop schizophrenia. Since astroglia are chiefly involved in the developmental organization, support and neurotransmission of neuronal networks, astrocyte pathology is thought to contribute to the aberrant neuronal traits widely documented in schizophrenia, such as disrupted neuronal development and connectivity, and dysregulated synaptic transmission. In recent studies, Goldman and colleagues engineered humanized glial chimeric mice using glial progenitor cells-derived from schizophrenia patients. These chimeric mice exhibited concomitant disease astroglial and schizophrenia behavioral phenotypes, while suppressing susceptibility genes significantly ameliorated the disease phenotype. These observations further support an astroglial basis on the genesis and pathology of schizophrenia. However, the precise influence of dysfunctional astroglia on the aberrant neuronal development and dysfunction in schizophrenia remains undetermined. Therefore, here, we will investigate the impact of schizophrenia (SCZ)- derived astroglia on neuronal network development and function using SCZ-glial mouse chimeras. To this end, I will employ serial electron microscopy to characterize changes in the ultrastructure of astroglia-neuron synaptic interactions and syncytial networks. I will also correlate previously identified gene expression patterns of SCZderived astroglia to their proteomic profile using mass spectrometry analysis. I will then establish the mechanistic influence of SCZ-astroglia on cell-intrinsic pathology and neuronal network dysfunction using electrophysiological recordings and calcium and glutamate imaging in the SCZ-astroglia chimeric brain. Results from this project will provide a better understanding on the influence of astrocyte pathology to the genesis and pathology of schizophrenia. My long-term research interest focuses on understanding the mechanisms regulating stem and progenitor cells to develop disease modeling and regenerative approaches for neuropsychiatric health disparities. Therefore, this training plan outlines the role of the sponsor and activities to promote the professional development, and ultimately facilitate my long-term professional goal of becoming an independent neuroscience investigator.