Harnessing Pluripotent Stem Cells to Study Neuropsychiatric Diseases
Material below is adapted from the SfN Short Course Developing Stem Cell Models to Study Neuropsychiatric Diseases, by Lindy Barrett, PhD, and Kevin Eggan, PhD. Short Courses are day-long scientific trainings on emerging neuroscience topics and research techniques held the day before SfN’s annual meeting.
Neuropsychiatric diseases are the leading cause of disability worldwide, affecting one in four people at some point in their lives. As a result of recent advances in DNA analysis technologies, scientists understand much more about the genetic basis of neuropsychiatric diseases such as schizophrenia, bipolar disorder, and autism spectrum disorder. However, the development of effective treatments for those disorders has been hindered by the lack of knowledge about how genetic variation affects the function of human brain cell types involved in behavior and cognition.
Human induced pluripotent stem cells (iPSCs) hold promise for patient-specific modeling of these disease processes. This approach involves genetically reprogramming adult cells, such as skin or blood cells from individual patients, to an embryonic stem cell–like state where they have the potential to become almost any cell in the body. When properly prodded, these “pluripotent” cells convert into mature cell types that retain the identical genetic makeup of the donor individual. Using iPSCs enables scientists to study how neuropsychiatric diseases impair the functioning of different cell types in the brain, to identify candidate drugs that show promise for correcting these cellular defects, and ultimately to develop new therapeutics.
Employing iPSCs to study the genetic basis of these complex and highly heritable neuropsychiatric diseases requires special consideration. For one, researchers need to take into account the synergistic effects of variation at multiple genetic loci, each of which explains only a fraction of the heritability of these illnesses. Moreover, they need to study variants across the allelic spectrum, from common to rare variants, and from large copy number variations to single nucleotide polymorphisms because these diverse classes of mutations act together to increase the risk of neuropsychiatric disease.
Scientists aren’t certain which diseases impact which cell types. Recently, researchers developed a highly efficient and reproducible protocol for converting human iPSCs into functional upper-layer neurons such as excitatory pyramidal neurons, which have been implicated in schizophrenia. By forcing the iPSCs to express the transcription factor neurorgin 2, scientist produced the excitatory pyramidal neurons in less than two weeks. This protocol allows researchers to further investigate the molecular, cellular, and physiological effects of specific genetic variants associated with schizophrenia and other psychiatric diseases.
In order to examine the neurobiological functions implicated in schizophrenia and other psychiatric diseases, researchers are turning to the CRISPR/Cas9 system, which has emerged in recent years as a flexible, accessible tool for precisely editing virtually any genomic site of interest. This technique makes it possible to engineer loss-of-function mutations or to insert desired DNA sequences into nearly any location in an organism’s genome, allowing researchers to study the role of various genes in neuropsychiatric diseases.
Scientists can’t yet create meaningful neural circuitry in a dish, limiting the ability to connect cellular dysfunction to behavior and cognition. Moreover, questions remain about the reproducibility and iPSCs and how representative they are of cells that are damaged in patients. Further technical advances that improve the reproducibility and utility of iPSCs could allow researchers to identify which brain cells are most affected by neuropsychiatric diseases and discover how these cells are malfunctioning. While our understanding of stem cell biology and the genetic contributors to neuropsychiatric diseases is at an early stage, iPSC technology could lay the foundation for identifying candidate drugs with corrective, therapeutic potential.