Manalac and K. DeLoach for technical assistance; the Stanford Transgenic Facility for help in generating mice; K. Beier, K. Deisseroth, L. DeNardo, X. Gao, C. Golgi, A. Huberman, N. Makki, A. Mizrahi, T. Mosca, L. Schwarz, and B. Weissbourd for helpful comments on the manuscript; and members of the Luo lab for helpful discussion. This

work was supported by grants from the National Institutes of Health (NIH; R01-NS050835 and TR01MH099647), the Simons Foundation, and by a Howard Hughes Medical Institute (HHMI) Collaborative Innovation Award. C.J.G. is supported by the U.S. Department of Defense through the National Defense Science and Engineering Graduate Fellowship program. H.H.Y. is a Stanford Graduate Fellow. K.M. was supported AG-014699 in vivo by the Human Frontier Science Program Organization (LT00300/2007-L). K.M. is a research specialist and L.L. is an investigator of the HHMI. “
“The generation of human embryonic stem cells (ESCs) and induced find more pluripotent stem cells (iPSCs) and their in vitro differentiation into

potentially any desired cell type hold great promise and may revolutionize the study of human disease (Hanna et al., 2010; Okita and Yamanaka, 2011; Blanpain et al., 2012). Given the lack of alternative sources, a major effort has been directed toward the development of differentiation protocols that convert pluripotent stem cells into neurons to allow examination of healthy human neurons and of neurons derived from patients with a variety of neurological diseases. In this approach, fibroblasts Ketanserin from patients with poorly understood diseases—such as schizophrenia or Alzheimer’s disease—are converted into iPSCs that are then differentiated into neurons to study the pathogenesis of these diseases (reviewed in Han et al., 2011; Ming et al., 2011; Brennand et al., 2012; Marchetto and Gage 2012). Moreover, elegant studies have described differentiation protocols that produce distinct types of neurons in vitro, although the number and properties of different types

of human neurons in situ are largely unknown and are only now beginning to be defined. Overall, these studies suggest that derivation of neurons from human stem cells may allow scientists to examine specific subtypes of neurons, to generate human neurons for regenerative medicine, and to investigate changes in human neurons in neuropsychiatric disorders (e.g., see Cho et al., 2008; Fasano et al., 2010; Kriks et al., 2011; Shi et al., 2012; Chambers et al., 2012; Ma et al., 2012). However, this approach of studying human neurons at present suffers from two major limitations. The first limitation is based on characteristic differences between particular pluripotent cell lines (Osafune et al., 2008; Hu et al., 2010; Bock et al., 2011). These differences influence the properties of the neurons that are derived from these lines. For example, neurons derived by the same protocol from two different ESC lines exhibited quite distinct properties (Wu et al., 2007).