Periodic Reporting for period 1 - Schizophrenia Organoids (Understanding the role of parvalbumin interneuron development in schizophrenia using human cerebral organoids)
Reporting period: 2017-09-01 to 2019-08-31
Schizophrenia is a devastating psychiatric disorder with an unclear cellular etiology. Genome association studies have produced a large list of genes associated with Schizophrenia, but the ability to test the function of these genes in neurobiology remains hindered by a lack of human experimental models. This is exemplified by the fact that many differences in various aspects of cortical development exist between human and rodents, one currently preferred experimental system. The advent of 3D culture models that can be generated from human pluripotent stem cells has revolutionized the generation of disease models. Combined with the recent innovation of 3D brain organoid culture models, complex models of various brain disorders are now being developed. This provides the opportunity to assess the function of disease associated genes in complex cellular behavior in developing brain-like tissue. The goal of the current study was to generate a 3D human brain organoid model of schizophrenia. Since the GABAergic interneuron subtype is highly implicated in the pathogenesis of schizophrenia, a second aim focused on analyzing the development of human GABAergic interneurons in the 3D brain organoid schizophrenia model.
The current study took advantage of the 3D brain organoid technology utilizing a human 3D model of GABAergic interneuron development. Using this 3D model of human interneuron development, a gene screening platform was developed using CRISPR/Cas9 genome engineering technology. By analyzing the transcriptome of migrating human interneurons in brain organoids, a candidate list of upregulated disease-associated genes was identified. The first gene tested was the schizophrenia-associated gene Erb-B2 receptor tyrosine kinase 4 (ERBB4), which when perturbed caused an alteration in the numbers of interneurons migrating into cortical tissue. These results were presented at several scientific conferences.
Since the list of schizophrenia-associated genes is growing and diverse, the ability to test the function of disease-associated genes in neural disease models is crucial to identifying the most essential genes implicated in disease pathogenesis. Combining the gene screening platform, and the candidate gene list allows for the first time the ability to test the function of disease-associated genes in regulating the migration of human interneurons. Therefore, this platform can be utilized to further test the role of additional genes in regulating human interneuron development, and possibly uncover cellular mechanisms of complex diseases such as schizophrenia. With a better cellular and molecular understanding of psychiatric disease states and etiology, more targeted therapies can be developed.