Gaining insight into psychiatric disease by engineering piece by piece the human brain in vitro.



 DESCRIPTION (provided by applicant): Most therapeutic advances in medicine are concentrated in accessible tissue disorders, such as coagulopathies and oncology, where diseased tissue can be directly examined and manipulated. To systematically and comprehensively study neuropsychiatric disorders at the molecular level, direct access to neurons and glia from patients is indispensable. Here, we propose to use an innovative approach that leverages a novel tridimensional (3D) neural differentiation method of human pluripotent stem cells (hiPSC), to separately generate neural spheroids that include either excitatory neurons of the cortex (subpallium-like) or ventral telencephalic interneurons (subpallium-like). Using regional-specific genetic enhancers, we plan to fluorescently label pallium-like and subpallium-like forebrain spheroids and fuse them to engineer mixed neural structures in suspension. Using a series of assays in two-region human forebrain spheroids engineered from hiPSC derived from patients with genetic forms of schizophrenia and autism spectrum disorders (ASD), we aim to identify the key pathophysiological processes underlying these disorders.