Collecting sufficient quantity or quality of human brain cells for biochemical and genetic analyses has been difficult. The development of human induced pluripotent stem cells (hiPSCs) provides a strategy to overcome this and is a compelling complement to animal models. hiPSCs are derived from donor somatic cells by reprogramming into a pluripotent state (Takahashi et al., 2007). These stem cells can then be differentiated into a desired cell type, e.g. an excitatory neuron. Once differentiated, cells derived from hiPSCs have the inherent advantage of containing all genes expressed endogenously under the correct tissue-specific promoters as well as non-coding regulatory sequences. Although variability within the whole genome, among multiple donors, poses a challenge to understanding single gene effects, hiPSCs are amenable to a variety of gene editing methods for probing individual or combinatorial gene contributions to a disease. Isogenic lines, which are genetically manipulated cells that have a single genetic background, can be generated to isolate the effects of one or more variants among simple variants or single SNPs. Gene knockouts in isogenic lines can be created to investigate the effects of reduced gene expression.
