Neuroinflammation and Neurogenesis in Schizophrenia

Project Summary The ability to generate immature neurons from neural stem cells is blunted in the brains of people with schizophrenia compared to controls. In this grant, we will determine, at the resolution of single cells, how the transcriptional profile of neurogenic cells is altered in schizophrenia in order to identify at which stage neurogenesis is blocked. Bulk RNA sequencing has identified that the most significantly changed transcript within the neurogenic niche in people with schizophrenia is the general macrophage marker, CD163. We will determine if macrophages in the neurogenic niche have the characteristics of helpful or harmful immune cells, and if the type of macrophage varies either with diagnosis (schizophrenia compared to controls) or based on the extent of local inflammation (high compared to low cytokines). We aim to gather evidence to support or negate possible monocyte migration routes across the blood-brain barrier (BBB). We will determine if brain macrophages have morphological features and molecular signatures consistent with differentiation into microglial-like cells, and if this varies with diagnosis. Lastly, we will determine if markers of adult neurogenesis are changed by inflammation and how glia cells may be changed by inflammation and/or by the presence of increased macrophages. By exploring the nature and transcriptomic state of different cell populations in the human neurogenic niche, we can better develop strategies to restore neurogenesis in schizophrenia and other neurological conditions, possibly through targeting macrophages.