Cell and Tissue Research

, Volume 371, Issue 1, pp 171–179 | Cite as

Single-cell analysis of diversity in human stem cell-derived neurons

  • Lise J. Harbom
  • Nadine Michel
  • Michael J. McConnell
Review

Abstract

Neural stem and progenitor cells produce one of the most remarkable organs in nature, the human brain. Among neural stem cell progeny, post-mitotic neurons are likewise remarkably diverse. Single-cell transcriptomic approaches are now cataloging a long-sought-after molecular taxonomy of neuronal diversity in the brain. Contemporary single-cell omic classifications of neuronal diversity build from electrophysiological approaches that for decades have measured and cataloged diverse biophysical properties of single neurons. With the widespread application of human pluripotent stem cell-based models of neurogenesis to investigate disease pathology and to develop new drugs, a high-resolution understanding of neuronal diversity in vivo is essential to benchmark the state of in vitro models of human neurological disease.

Keywords

Neural development Neuronal diversity Single-cell analysis Neural stem cells Pluripotent stem cells 

Notes

Acknowledgements

We thank M. Beenhakker for helpful insights into the history of the patch-clamp technique and assessment of neuronal diversity by electrophysiological methods. We also acknowledge that the single-cell field is rapidly evolving and apologize, in advance, to many colleagues whose advances in single-cell measurement of neuronal diversity will undoubtably be reported after this review was prepared. This work was supported by NIMH U01 MH106882 to M.J.M., NIGMS T32 GM008328-24 to L.J.H., and T32 GM008136-30 to N.M.

References

  1. Avaliani N, Sorensen AT, Ledri M, Bengzon J, Koch P, Brustle O, … Kokaia M (2014) Optogenetics reveal delayed afferent synaptogenesis on grafted human-induced pluripotent stem cell-derived neural progenitors. Stem Cells 32(12):3088–3098. doi: https://doi.org/10.1002/stem.1823
  2. Baillie JK, Barnett MW, Upton KR, Gerhardt DJ, Richmond TA, De Sapio F., … Faulkner GJ (2011) Somatic retrotransposition alters the genetic landscape of the human brain. Nature, 479(7374):534–537. doi: https://doi.org/10.1038/nature10531
  3. Bandura DR, Baranov VI, Ornatsky OI, Antonov A, Kinach R, Lou X, … Tanner SD (2009) Mass cytometry: technique for real time single cell multitarget immunoassay based on inductively coupled plasma time-of-flight mass spectrometry. Anal Chem 81(16):6813–6822. doi: https://doi.org/10.1021/ac901049w
  4. Bardy C, van den Hurk M, Eames T, Marchand C, Hernandez RV, Kellogg M, … Gage FH (2015) Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro. Proc Natl Acad Sci USA 112(20):E2725–2734. doi: https://doi.org/10.1073/pnas.1504393112
  5. Bardy C, van den Hurk M, Kakaradov B, Erwin JA, Jaeger BN, Hernandez RV, … Gage FH (2016) Predicting the functional states of human iPSC-derived neurons with single-cell RNA-seq and electrophysiology. Mol Psychiatry 21(11):1573–1588. doi: https://doi.org/10.1038/mp.2016.158
  6. Belinsky GS, Rich MT, Sirois CL, Short SM, Pedrosa E, Lachman HM, Antic SD (2014) Patch-clamp recordings and calcium imaging followed by single-cell PCR reveal the developmental profile of 13 genes in iPSC-derived human neurons. Stem Cell Res 12(1):101–118.  https://doi.org/10.1016/j.scr.2013.09.014 CrossRefPubMedGoogle Scholar
  7. Bendall SC, Davis KL, Amir el-AD., Tadmor MD, Simonds EF, Chen TJ., … Pe'er D (2014) Single-cell trajectory detection uncovers progression and regulatory coordination in human B cell development. Cell 157(3):714–725. doi: https://doi.org/10.1016/j.cell.2014.04.005
  8. Bock C, Farlik M, Sheffield NC (2016) Multi-Omics of single cells: strategies and applications. Trends Biotechnol 34(8):605–608.  https://doi.org/10.1016/j.tibtech.2016.04.004 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Brennand K, Savas JN., Kim, Y., Tran, N., Simone, A., Hashimoto-Torii, K., … Gage, F. H. (2015a) Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry 20(3):361–368. doi: https://doi.org/10.1038/mp.2014.22
  10. Brennand, K. J., Marchetto, M. C., Benvenisty, N., Brustle, O., Ebert, A., Izpisua Belmonte, J. C., … Jaenisch, R. (2015b) Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders. Stem Cell Reports 5(6):933–945. doi: https://doi.org/10.1016/j.stemcr.2015.10.011
  11. Brennand, K. J., Simone, A., Jou, J., Gelboin-Burkhart, C., Tran, N., Sangar, S., … Gage, F. H. (2011) Modelling schizophrenia using human induced pluripotent stem cells. Nature 473(7346):221–225. doi: https://doi.org/10.1038/nature09915
  12. Budnik BLE, Slavov N (2017) Mass-spectrometry of single mammalian cells quantifies proteome heterogeneity during cell differentiation. bioRxiv.  https://doi.org/10.1101/102681
  13. Cadwell, C. R., Palasantza, A., Jiang, X., Berens, P., Deng, Q., Yilmaz, M., … Tolias, A. S. (2016) Electrophysiological, transcriptomic and morphologic profiling of single neurons using Patch-seq. Nat Biotechnol 34(2):199–203. doi: https://doi.org/10.1038/nbt.3445
  14. Cai X, Evrony GD, Lehmann HS, Elhosary PC, Mehta BK, Poduri A, Walsh CA (2014) Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. Cell Rep 8(5):1280–1289.  https://doi.org/10.1016/j.celrep.2014.07.043 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Cajal S (1890) Textura de las circunvoluticiones cerebrales de los mamiferos inferiores. Gaceta Medica Catalana:22–31Google Scholar
  16. Cajal, S. (1891) Sur la structure de l'ecorce cerebrale de quelques mammiferes. La Cellule, 125–176Google Scholar
  17. Connors BW, Gutnick MJ (1990) Intrinsic firing patterns of diverse neocortical neurons. Trends Neurosci 13(3):99–104CrossRefPubMedGoogle Scholar
  18. Contreras D (2004) Electrophysiological classes of neocortical neurons. Neural Netw 17(5–6):633–646.  https://doi.org/10.1016/j.neunet.2004.04.003 CrossRefPubMedGoogle Scholar
  19. Coufal, N. G., Garcia-Perez, J. L., Peng, G. E., Yeo, G. W., Mu, Y., Lovci, M. T., … Gage, F. H. (2009) L1 retrotransposition in human neural progenitor cells. Nature 460(7259):1127–1131. doi: https://doi.org/10.1038/nature08248
  20. Dulken BW, Leeman DS, Boutet SC, Hebestreit K, Brunet A (2017) Single-cell Transcriptomic analysis defines heterogeneity and transcriptional dynamics in the adult neural stem cell lineage. Cell Rep 18(3):777–790.  https://doi.org/10.1016/j.celrep.2016.12.060 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Eberwine J, Kim J (2015) Cellular deconstruction: finding meaning in individual cell variation. Trends Cell Biol 25(10):569–578.  https://doi.org/10.1016/j.tcb.2015.07.004 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Erwin, J. A., Paquola, A. C., Singer, T., Gallina, I., Novotny, M., Quayle, C., … Gage, F. H. (2016) L1-associated genomic regions are deleted in somatic cells of the healthy human brain. Nat Neurosci 19(12):1583–1591. doi: https://doi.org/10.1038/nn.4388
  23. Espuny-Camacho, I., Michelsen, K. A., Gall, D., Linaro, D., Hasche, A., Bonnefont, J., … Vanderhaeghen, P. (2013) Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo. Neuron 77(3):440–456. doi: https://doi.org/10.1016/j.neuron.2012.12.011
  24. Evrony, G. D., Cai, X., Lee, E., Hills, L. B., Elhosary, P. C., Lehmann, H. S., … Walsh, C. A. (2012) Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell 151(3):483–496. doi: https://doi.org/10.1016/j.cell.2012.09.035
  25. Farlik M, Sheffield NC, Nuzzo A, Datlinger P, Schonegger A, Klughammer J, Bock C (2015) Single-cell DNA methylome sequencing and bioinformatic inference of epigenomic cell-state dynamics. Cell Rep 10(8):1386–1397.  https://doi.org/10.1016/j.celrep.2015.02.001 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Foldy C, Darmanis S, Aoto J, Malenka RC, Quake SR, Sudhof TC (2016) Single-cell RNAseq reveals cell adhesion molecule profiles in electrophysiologically defined neurons. Proc Natl Acad Sci U S A 113(35):E5222–E5231.  https://doi.org/10.1073/pnas.1610155113 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Fuzik, J., Zeisel, A., Mate, Z., Calvigioni, D., Yanagawa, Y., Szabo, G., … Harkany, T. (2016) Integration of electrophysiological recordings with single-cell RNA-seq data identifies neuronal subtypes. Nat Biotechnol 34(2):175–183. doi: https://doi.org/10.1038/nbt.3443
  28. Gobel W, Kampa BM, Helmchen F (2007) Imaging cellular network dynamics in three dimensions using fast 3D laser scanning. Nat Methods 4(1):73–79.  https://doi.org/10.1038/nmeth989 CrossRefPubMedGoogle Scholar
  29. Golgi C (1886) Sulla Fina Anatomia degli Organi Centrali del Sistema Nervosa. U. Hoepli, MilanoGoogle Scholar
  30. Gravina S, Dong X, Yu B, Vijg J (2016) Single-cell genome-wide bisulfite sequencing uncovers extensive heterogeneity in the mouse liver methylome. Genome Biol 17(1):150.  https://doi.org/10.1186/s13059-016-1011-3 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Grindberg, R. V., Yee-Greenbaum, J. L., McConnell, M. J., Novotny, M., O'Shaughnessy, A. L., Lambert, G. M., … Lasken, R. S. (2013) RNA-sequencing from single nuclei. Proc Natl Acad Sci U S A 110(49):19802–19807. doi: https://doi.org/10.1073/pnas.1319700110
  32. Handel, A. E., Chintawar, S., Lalic, T., Whiteley, E., Vowles, J., Giustacchini, A., … Cader, M. Z. (2016) Assessing similarity to primary tissue and cortical layer identity in induced pluripotent stem cell-derived cortical neurons through single-cell transcriptomics. Hum Mol Genet 25(5):989–1000. doi: https://doi.org/10.1093/hmg/ddv637
  33. Hazen, J. L., Faust, G. G., Rodriguez, A. R., Ferguson, W. C., Shumilina, S., Clark, R. A., … Baldwin, K. K. (2016) The Complete Genome Sequences, Unique Mutational Spectra, and Developmental Potency of Adult Neurons Revealed by Cloning. Neuron 89(6):1223–1236. doi: https://doi.org/10.1016/j.neuron.2016.02.004
  34. Johnson MB, Wang PP, Atabay KD, Murphy EA, Doan RN, Hecht JL, Walsh CA (2015) Single-cell analysis reveals transcriptional heterogeneity of neural progenitors in human cortex. Nat Neurosci 18(5):637–646.  https://doi.org/10.1038/nn.3980 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Kemp, P. J., Rushton, D. J., Yarova, P. L., Schnell, C., Geater, C., Hancock, J. M., … Telezhkin, V. (2016) Improving and accelerating the differentiation and functional maturation of human stem cell-derived neurons: role of extracellular calcium and GABA. J Physiol 594(22):6583–6594. doi: https://doi.org/10.1113/JP270655
  36. Knouse KA, Wu J, Amon A (2016) Assessment of megabase-scale somatic copy number variation using single-cell sequencing. Genome Res 26(3):376–384.  https://doi.org/10.1101/gr.198937.115 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Kuijlaars, J., Oyelami, T., Diels, A., Rohrbacher, J., Versweyveld, S., Meneghello, G., … Verheyen, A. (2016) Sustained synchronized neuronal network activity in a human astrocyte co-culture system. Sci Rep 6:36529. doi: https://doi.org/10.1038/srep36529
  38. Kuwabara, T., Hsieh, J., Muotri, A., Yeo, G., Warashina, M., Lie, D. C., … Gage, F. H. (2009) Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis. Nat Neurosci 12(9):1097–1105. doi: https://doi.org/10.1038/nn.2360
  39. Lacar, B., Linker, S. B., Jaeger, B. N., Krishnaswami, S., Barron, J., Kelder, M., … Gage, F. H. (2016) Nuclear RNA-seq of single neurons reveals molecular signatures of activation. Nat Commun 7:11022. doi: https://doi.org/10.1038/ncomms11022
  40. Lake, B. B., Ai, R., Kaeser, G. E., Salathia, N. S., Yung, Y. C., Liu, R., … Zhang, K. (2016) Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain. Science 352(6293):1586–1590. doi: https://doi.org/10.1126/science.aaf1204
  41. Lam RS, Topfer FM, Wood PG, Busskamp V, Bamberg E (2017) Functional maturation of human stem cell-derived neurons in long-term cultures. PLoS One 12(1):e0169506.  https://doi.org/10.1371/journal.pone.0169506 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Lancaster, M. A., Renner, M., Martin, C. A., Wenzel, D., Bicknell, L. S., Hurles, M. E., … Knoblich, J. A. (2013) Cerebral organoids model human brain development and microcephaly. Nature 501(7467):373–379. doi: https://doi.org/10.1038/nature12517
  43. Linnarsson S (2013) Single-cell biology meeting marks rebirth of an old science. Genome Biol 14(4):305.  https://doi.org/10.1186/gb-2013-14-4-305 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Liu, S. J., Nowakowski, T. J., Pollen, A. A., Lui, J. H., Horlbeck, M. A., Attenello, F. J., … Lim, D. A. (2016) Single-cell analysis of long non-coding RNAs in the developing human neocortex. Genome Biol 17:67. doi: https://doi.org/10.1186/s13059-016-0932-1
  45. Liu, Y., Lopez-Santiago, L. F., Yuan, Y., Jones, J. M., Zhang, H., O'Malley, H. A., … Parent, J. M. (2013) Dravet syndrome patient-derived neurons suggest a novel epilepsy mechanism. Ann Neurol 74(1):128–139. doi: https://doi.org/10.1002/ana.23897
  46. Livesey MR, Magnani D, Hardingham GE, Chandran S, Wyllie DJ (2016) Functional properties of in vitro excitatory cortical neurons derived from human pluripotent stem cells. J Physiol 594(22):6573–6582.  https://doi.org/10.1113/JP270660 CrossRefPubMedGoogle Scholar
  47. Lodato, M. A., Woodworth, M. B., Lee, S., Evrony, G. D., Mehta, B. K., Karger, A., … Walsh, C. A. (2015) Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 350(6256):94–98. doi: https://doi.org/10.1126/science.aab1785
  48. Lodato S, Arlotta P (2015) Generating neuronal diversity in the mammalian cerebral cortex. Annu Rev Cell Dev Biol 31:699–720.  https://doi.org/10.1146/annurev-cellbio-100814-125353 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Lui JH, Hansen DV, Kriegstein AR (2011) Development and evolution of the human neocortex. Cell 146(1):18–36.  https://doi.org/10.1016/j.cell.2011.06.030 CrossRefPubMedPubMedCentralGoogle Scholar
  50. Lynch M (2010) Rate, molecular spectrum, and consequences of human mutation. Proc Natl Acad Sci U S A 107(3):961–968.  https://doi.org/10.1073/pnas.0912629107 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Macaulay IC, Ponting CP, Voet T (2017) Single-cell Multiomics: multiple measurements from single cells. Trends Genet 33(2):155–168.  https://doi.org/10.1016/j.tig.2016.12.003 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Macaulay IC, Voet T (2014) Single cell genomics: advances and future perspectives. PLoS Genet 10(1):e1004126.  https://doi.org/10.1371/journal.pgen.1004126 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Macosko, E. Z., Basu, A., Satija, R., Nemesh, J., Shekhar, K., Goldman, M., … McCarroll, S. A. (2015) Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell 161(5):1202–1214. doi: https://doi.org/10.1016/j.cell.2015.05.002
  54. Mainen ZF, Sejnowski TJ (1996) Influence of dendritic structure on firing pattern in model neocortical neurons. Nature 382(6589):363–366.  https://doi.org/10.1038/382363a0 CrossRefPubMedGoogle Scholar
  55. Manganas, L. N., Zhang, X., Li, Y., Hazel, R. D., Smith, S. D., Wagshul, M. E., … Maletic-Savatic, M. (2007) Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science 318(5852):980–985. doi: https://doi.org/10.1126/science.1147851
  56. Mariani, J., Simonini, M. V., Palejev, D., Tomasini, L., Coppola, G., Szekely, A. M., … Vaccarino, F. M. (2012) Modeling human cortical development in vitro using induced pluripotent stem cells. Proc Natl Acad Sci U S A 109(31):12770–12775. doi: https://doi.org/10.1073/pnas.1202944109
  57. Masland RH (2004) Neuronal cell types. Curr Biol 14(13):R497–R500.  https://doi.org/10.1016/j.cub.2004.06.035 CrossRefPubMedGoogle Scholar
  58. Mason A, Larkman A (1990) Correlations between morphology and electrophysiology of pyramidal neurons in slices of rat visual cortex. II. Electrophysiology. J Neurosci 10(5):1415–1428PubMedGoogle Scholar
  59. McConnell, M. J., Lindberg, M. R., Brennand, K. J., Piper, J. C., Voet, T., Cowing-Zitron, C., … Gage, F. H. (2013) Mosaic copy number variation in human neurons. Science 342(6158):632–637. doi: https://doi.org/10.1126/science.1243472
  60. McConnell, M. J., Moran, J. V., Abyzov, A., Akbarian, S., Bae, T., Cortes-Ciriano, I., … Brain Somatic Mosaicism, N. (2017). Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network. Science 356(6336). doi: https://doi.org/10.1126/science.aal1641
  61. Migliore M, Shepherd GM (2005) Opinion: an integrated approach to classifying neuronal phenotypes. Nat Rev Neurosci 6(10):810–818.  https://doi.org/10.1038/nrn1769 CrossRefPubMedGoogle Scholar
  62. Mizrahi A (2007) Dendritic development and plasticity of adult-born neurons in the mouse olfactory bulb. Nat Neurosci 10(4):444–452.  https://doi.org/10.1038/nn1875 PubMedGoogle Scholar
  63. Moore AR, Filipovic R, Mo Z, Rasband MN, Zecevic N, Antic SD (2009) Electrical excitability of early neurons in the human cerebral cortex during the second trimester of gestation. Cereb Cortex 19(8):1795–1805.  https://doi.org/10.1093/cercor/bhn206 CrossRefPubMedGoogle Scholar
  64. Mountcastle VB, Talbot WH, Sakata H, Hyvarinen J (1969) Cortical neuronal mechanisms in flutter-vibration studied in unanesthetized monkeys. Neuronal periodicity and frequency discrimination. J Neurophysiol 32(3):452–484CrossRefPubMedGoogle Scholar
  65. Muller, F. J., Schuldt, B. M., Williams, R., Mason, D., Altun, G., Papapetrou, E. P., … Loring, J. F. (2011) A bioinformatic assay for pluripotency in human cells. Nat Methods 8(4):315–317. doi: https://doi.org/10.1038/nmeth.1580
  66. Namba, T., & Huttner, W. B. (2017) Neural progenitor cells and their role in the development and evolutionary expansion of the neocortex. Wiley Interdiscip Rev Dev Biol 6(1). doi: https://doi.org/10.1002/wdev.256
  67. Neher E, Sakmann B (1976) Single-channel currents recorded from membrane of denervated frog muscle fibres. Nature 260(5554):799–802CrossRefPubMedGoogle Scholar
  68. Pasca, A. M., Sloan, S. A., Clarke, L. E., Tian, Y., Makinson, C. D., Huber, N., … Pasca, S. P. (2015) Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods 12(7):671–678. doi: https://doi.org/10.1038/nmeth.3415
  69. Pruszak J, Sonntag KC, Aung MH, Sanchez-Pernaute R, Isacson O (2007) Markers and methods for cell sorting of human embryonic stem cell-derived neural cell populations. Stem Cells 25(9):2257–2268.  https://doi.org/10.1634/stemcells.2006-0744 CrossRefPubMedPubMedCentralGoogle Scholar
  70. Randall AD (2016) Are stem cell-derived neural cells physiologically credible? J Physiol 594(22):6569–6572.  https://doi.org/10.1113/JP273348 CrossRefPubMedPubMedCentralGoogle Scholar
  71. Rushton DJ, Mattis VB, Svendsen CN, Allen ND, Kemp PJ (2013) Stimulation of GABA-induced Ca2+ influx enhances maturation of human induced pluripotent stem cell-derived neurons. PLoS ONE 8(11):e81031.  https://doi.org/10.1371/journal.pone.0081031 CrossRefPubMedPubMedCentralGoogle Scholar
  72. Schroeder T (2011) Long-term single-cell imaging of mammalian stem cells. Nat Methods 8(4 Suppl):S30–S35.  https://doi.org/10.1038/nmeth.1577 CrossRefPubMedGoogle Scholar
  73. Song M, Mohamad O, Chen D, Yu SP (2013) Coordinated development of voltage-gated Na+ and K+ currents regulates functional maturation of forebrain neurons derived from human induced pluripotent stem cells. Stem Cells Dev 22(10):1551–1563.  https://doi.org/10.1089/scd.2012.0556 CrossRefPubMedGoogle Scholar
  74. Steriade M (2004) Neocortical cell classes are flexible entities. Nat Rev Neurosci 5(2):121–134.  https://doi.org/10.1038/nrn1325 CrossRefPubMedGoogle Scholar
  75. Tang X, Zhou L, Wagner AM, Marchetto MC, Muotri AR, Gage FH, Chen G (2013) Astroglial cells regulate the developmental timeline of human neurons differentiated from induced pluripotent stem cells. Stem Cell Res 11(2):743–757.  https://doi.org/10.1016/j.scr.2013.05.002 CrossRefPubMedPubMedCentralGoogle Scholar
  76. Tasic, B., Menon, V., Nguyen, T. N., Kim, T. K., Jarsky, T., Yao, Z., … Zeng, H. (2016) Adult mouse cortical cell taxonomy revealed by single cell transcriptomics. Nat Neurosci 19(2):335–346. doi: https://doi.org/10.1038/nn.4216
  77. Tsankov, A. M., Akopian, V., Pop, R., Chetty, S., Gifford, C. A., Daheron, L., … Meissner, A. (2015) A qPCR ScoreCard quantifies the differentiation potential of human pluripotent stem cells. Nat Biotechnol 33(11):1182–1192. doi: https://doi.org/10.1038/nbt.3387
  78. Tyler WA, Medalla M, Guillamon-Vivancos T, Luebke JI, Haydar TF (2015) Neural precursor lineages specify distinct neocortical pyramidal neuron types. J Neurosci 35(15):6142–6152.  https://doi.org/10.1523/JNEUROSCI.0335-15.2015 CrossRefPubMedPubMedCentralGoogle Scholar
  79. Upton, K. R., Gerhardt, D. J., Jesuadian, J. S., Richardson, S. R., Sanchez-Luque, F. J., Bodea, G. O., … Faulkner, G. J. (2015) Ubiquitous L1 mosaicism in hippocampal neurons. Cell 161(2):228–239. doi: https://doi.org/10.1016/j.cell.2015.03.026
  80. Yokota Y, Gashghaei HT, Han C, Watson H, Campbell KJ, Anton ES (2007) Radial glial dependent and independent dynamics of interneuronal migration in the developing cerebral cortex. PLoS ONE 2(8):e794.  https://doi.org/10.1371/journal.pone.0000794 CrossRefPubMedPubMedCentralGoogle Scholar
  81. Yu YC, Bultje RS, Wang X, Shi SH (2009) Specific synapses develop preferentially among sister excitatory neurons in the neocortex. Nature 458(7237):501–504.  https://doi.org/10.1038/nature07722 CrossRefPubMedPubMedCentralGoogle Scholar
  82. Zeisel, A., Munoz-Manchado, A. B., Codeluppi, S., Lonnerberg, P., La Manno, G., Jureus, A., … Linnarsson, S. (2015) Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 347(6226):1138–1142. doi: https://doi.org/10.1126/science.aaa1934
  83. Zhu G, Du L, Jin L, Offenhausser A (2016) Effects of morphology constraint on electrophysiological properties of cortical neurons. Sci Rep 6:23086.  https://doi.org/10.1038/srep23086 CrossRefPubMedPubMedCentralGoogle Scholar
  84. Zunder ER, Lujan E, Goltsev Y, Wernig M, Nolan GP (2015) A continuous molecular roadmap to iPSC reprogramming through progression analysis of single-cell mass cytometry. Cell Stem Cell 16(3):323–337.  https://doi.org/10.1016/j.stem.2015.01.015 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Lise J. Harbom
    • 1
  • Nadine Michel
    • 1
  • Michael J. McConnell
    • 1
  1. 1.Department of Biochemistry and Molecular Genetics, Neuroscience Graduate ProgramUniversity of Virginia School of MedicineCharlottesvilleUSA

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