The balance between excitation and inhibition is crucial for brain function. Converging findings indicate that perturbation in the excitatory-inhibitory balance exists in many psychiatric disorders. However, due to the inaccessibility of the human brain, most studies on neuropsychiatric disorders have relied on animal models. To date, human studies of these psychiatric disorders have been restricted to brain imaging and postmortem studies. The generation of human embryonic stem cells ES cells) and induced pluripotent stem iPS) cells and their in vitro differentiation into potentially any desired cell type holds great promise to revolutionize the study of human neuropsychiatric disorders. However, the current differentiation procedures give variable results and are time- and labor- consuming.
In this study, we propose to generate human inhibitory neurons, a vulnerable population of neurons that are affected in many psychiatric disorders including Autism Spectrum Disease ASD), from pluripotent stem cells and use this approach to explore the cellular phenotype associated with neuropsychiatric disorders. We will first establish methods that allow highly efficient conversion of human pluripotent cells into inhibitory neurons through forced expression of lineage-specific transcription factors. Then, we will make human embryonic stem ES) cell line with a mutation associated with ASD as well as the control isogenic ES cells for sophisticated functional studies that will provide mechanistic insights into this human disease.
Given the promising preliminary results we have obtained and the phenotype observed in mouse model, we believe it is feasible to generate and characterize functional inhibitory neurons from pluripotent stem cells using the forced expression of inhibitory neuron specific transcription factors. Our approach that utilizes a renewable resource and results in neurons cells with reproducible properties that are independent of the starting cell line can be used not only to study the cellular phenotype associated with neuropsychiatric disorders, but also for drug screening endeavors and mechanistic studies.