Derivation of cortical interneurons from human pluripotent stem cells to model neurodevelopmental disorders

Human pluripotent stem cell (hPSC)-derived neurons provide a valuable platform for modeling altered neuronal physiology, development, and function that contribute to neurodevelopmental disorders. These models effectively recapitulate human subject-specific contributors to disease and can also assess interventions to reverse these phenotypes. However, most extant studies model neurodevelopmental disorders only in hPSC-derived cortical excitatory neurons, while disruption of other disease-relevant neuronal cell types, including inhibitory GABAergic cortical interneurons, may contribute significantly to disease. Here, we describe the development of protocols for hPSC differentiation into cortical interneurons and the relationship of this differentiation protocol to aspects of human fetal brain development. We provide a detailed step-by-step protocol for cortical interneuron derivation from hPSCs and describe common phenotyping assays to identify alterations of this developmental program often associated with neurodevelopmental disorders. These protocols broaden the phenotyping that can be applied to hPSC models and our capacity to elucidate underlying contributors to neurodevelopmental disorders.