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Origin of GABAergic neurons in the human neocortex

Abstract

The mammalian neocortex contains two major classes of neurons, projection and local circuit neurons1,2,3,4. Projection neurons contain the excitatory neurotransmitter glutamate, while local circuit neurons are inhibitory, containing GABA2,4. The complex function of neocortical circuitry depends on the number and diversity of GABAergic (γ-aminobutyric-acid-releasing) local circuit neurons1,2,3. Using retroviral labelling in organotypic slice cultures of the embryonic human forebrain, we demonstrate the existence of two distinct lineages of neocortical GABAergic neurons. One lineage expresses Dlx1/2 and Mash1 transcription factors, represents 65% of neocortical GABAergic neurons in humans, and originates from Mash1-expressing progenitors of the neocortical ventricular and subventricular zone of the dorsal forebrain. The second lineage, characterized by the expression of Dlx1/2 but not Mash1, forms around 35% of the GABAergic neurons and originates from the ganglionic eminence of the ventral forebrain. We suggest that modifications in the expression pattern of transcription factors in the forebrain may underlie species-specific programmes for the generation of neocortical local circuit neurons5,6,7,8,9,10,11 and that distinct lineages of cortical interneurons may be differentially affected in genetic and acquired diseases of the human brain.

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Figure 1: Mode of migration of GABAergic neurons in the fetal human neocortex.
Figure 2: Mash1-expression in neocortical GABAergic neurons and VZ/SVZ progenitors.
Figure 3: Neocortical lineage of GABAergic neurons and their progenitors revealed by a retroviral analysis in living slices.
Figure 4: Neocortical GABAergic neurons originating in the GE.

References

  1. 1

    Ramon y Cajal, S. R. Histologie du Système Nerveux de l'Homme et des Vertébrés (Maloine, Paris, 1911)

    Google Scholar 

  2. 2

    Rakic, P. Local circuit neurons. Neurosci. Res. Prog. Bull. 13, 1–399 (1975)

    Google Scholar 

  3. 3

    Gupta, A., Wang, Y. & Markram, H. Organizing principle for diversity of GABAergic interneurons and synapses in the neocortex. Science 287, 273–278 (2000)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Fairen, A., DeFelipe, J. & Regidor, J. in Cellular Components of the Cerebral Cortex (eds Peters, A. & Jones, E. G.) 201–253 (Plenum, New York, 1984)

    Google Scholar 

  5. 5

    Marin, O., Yaron, A., Bagri, A., Tessier-Lavigne, M. & Rubenstein, J. L. R. Sorting of striatal and cortical interneurons regulated by semaphorin-neuropilin interactions. Science 293, 872–875 (2001)

    CAS  Article  Google Scholar 

  6. 6

    Tan, S. S. et al. Separate progenitors for radial and tangential cell dispersion during development of the cerebral neocortex. Neuron 21, 295–304 (1998)

    CAS  Article  Google Scholar 

  7. 7

    Ware, M. L., Tavazoie, S. F., Reid, C. B. & Walsh, C. A. Coexistence of widespread clones and large radial clones in early embryonic ferret cortex. Cereb. Cortex. 9, 636–645 (1999)

    CAS  Article  Google Scholar 

  8. 8

    de Carlos, J. A., López-Mascaraque, L. & Valverde, F. Dynamics of cell migration from the lateral ganglionic eminence in the rat. J. Neurosci. 16, 6146–6156 (1996)

    CAS  Article  Google Scholar 

  9. 9

    Powel, E. M., Mara, W. M. & Levitt, P. Hepatocyte growth factor/scatter factor is mitogen for interneuron migrating from the ventral to dorsal telencephaon. Neuron 30, 1–20 (2001)

    Article  Google Scholar 

  10. 10

    Anderson, S., Mione, M., Yun, K. & Rubenstein, J. L. R. Differential origins of neocortical projection and local circuit neurons: Role of Dlx genes in neocortical interneuronogenesis. Cereb. Cortex 9, 646–654 (1999)

    CAS  Article  Google Scholar 

  11. 11

    Lavdas, A. A., Grigoriou, M., Pachnis, V. & Parnavelas, J. G. The medial ganglionic eminence gives rise to a population of early neurons in the developing cerebral cortex. J. Neurosci. 19, 7881–7888 (1999)

    CAS  Article  Google Scholar 

  12. 12

    Rakic, P. Mode of cell migration to the superficial layers of fetal monkey neocortex. J. Comp. Neurol. 145, 61–84 (1972)

    CAS  Article  Google Scholar 

  13. 13

    Luskin, M. B., Pearlman, A. L. & Sanes, J. R. Cell lineage in the cerebral cortex of the mouse studied in vivo and in vitro with recombinant retrovirus. Neuron 1, 635–647 (1988)

    CAS  Article  Google Scholar 

  14. 14

    Kornack, D. R. & Rakic, P. Radial and horizontal deployment of clonally related cells in the primate neocortex: Relationship to distinct mitotic lineages. Neuron 15, 311–321 (1995)

    CAS  Article  Google Scholar 

  15. 15

    Neyt, C., Welch, M., Langston, A., Kohtz, J. & Fishell, G. A short-range signal restricts cell movement between telencephalic proliferative zones. J. Neurosci. 17, 9194–9203 (1997)

    CAS  Article  Google Scholar 

  16. 16

    O'Rourke, N. A., Chenn, A. & McConnell, S. K. Postmitotic neurons migrate tangentially in the cortical ventricular zone. Development 124, 997–1005 (1997)

    CAS  PubMed  Google Scholar 

  17. 17

    He, W., Ingraham, C., Rising, L., Goderie, S. & Temple, S. Multipotent stem cells from the mouse basal forebrain contribute GABAergic neurons and oligodendrocytes to the cerebral cortex during embryogenesis. J. Neurosci. 21, 8854–8862 (2001)

    CAS  Article  Google Scholar 

  18. 18

    Casarosa, S., Fode, C. & Guillemot, F. Mash1 regulates neurogenesis in the ventral telencephalon. Development 126, 525–534 (1999)

    CAS  PubMed  Google Scholar 

  19. 19

    Horton, S., Meredith, A., Richardson, J. A. & Johnson, J. E. Correct coordination of neuronal differentiation events in ventral forebrain requires the bHLH factor MASH1. Mol. Cell. Neurosci. 14, 355–369 (1999)

    CAS  Article  Google Scholar 

  20. 20

    Hendry, S. H. & Carder, R. K. Neurochemical compartmentation of monkey and human visual cortex; similarities and variations in calbindin immunoreactivity across species. Vis. Neurosci. 10, 1109–1120 (1993)

    CAS  Article  Google Scholar 

  21. 21

    Jones, E. G. GABAergic neurons and their role in cortical plasticity in primates. Cereb. Cortex 3, 361–372 (1993)

    CAS  Article  Google Scholar 

  22. 22

    Sidman, R. L. & Rakic, P. Neuronal migration, with special reference to developing human brain: A review. Brain Res. 62, 1–35 (1973)

    CAS  Article  Google Scholar 

  23. 23

    Fode, C. et al. A role for neural determination genes in specifying the dorsoventral identity of telencephalic neurons. Genes Dev. 14, 67–80 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Tarabykin, V., Stoykova, A., Usman, N. & Gruss, P. Cortical upper layer neurons derive from the subventricular zone as indicated by Svet1 gene expression. Development 128, 1983–1993 (2001)

    CAS  PubMed  Google Scholar 

  25. 25

    Kakita, A. & Goldman, J. Patterns and dynamics of SVZ cell migration in the postnatal forebrain: monitoring living progenitors in slice preparations. Neuron 23, 461–472 (1999)

    CAS  Article  Google Scholar 

  26. 26

    Preuss, T. Taking the measure of diversity: comparative alternatives in the model-animal paradigm in cortical neuroscience. Brain Behav. Evol. 55, 287–299 (2000)

    CAS  Article  Google Scholar 

  27. 27

    Rakic, P. Specification of cerebral cortical areas. Science 241, 170–176 (1988)

    ADS  CAS  Article  Google Scholar 

  28. 28

    Gleeson, J. G. & Walsh, C. A. Neuronal migration disorders: From genetic diseases to developmental mechanisms. Trends Neurosci. 23, 352–359 (2000)

    CAS  Article  Google Scholar 

  29. 29

    Jones, E. G. Cortical development and thalamic pathology in schizophrenia. Schizophr. Bull. 23, 483–501 (1997)

    CAS  Article  Google Scholar 

  30. 30

    Lewis, D. A. GABAergic local circuit neurons and prefrontal cortical dysfunction in schizophrenia. Brain Res. Rev. 31, 270–276 (2000)

    ADS  CAS  Article  Google Scholar 

  31. 31

    Haydar, T. F., Bambrick, L. L., Kruger, B. K. & Rakic, P. Embryonic organotypic slice cultures for analysis of proliferation, cell death and migration in the cerebral wall. Brain Res. Protocols 4, 425–437 (1999)

    CAS  Article  Google Scholar 

  32. 32

    Letinic, K. & Rakic, P. Telencephalic origin of human thalamic GABAergic neurons. Nature Neurosci. 4, 931–936 (2001)

    CAS  Article  Google Scholar 

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Acknowledgements

We thank J. E. Johnson for providing Mash1 antibodies and J. L. R. Rubenstein and S. Anderson for providing Dlx1/2 antibodies. We also thank F. Miller for providing Ta1-LacZ plasmid. We are grateful to all colleagues in the laboratory of P. R. for their advice and comments on the manuscript.

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Correspondence to Pasko Rakic.

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Letinic, K., Zoncu, R. & Rakic, P. Origin of GABAergic neurons in the human neocortex. Nature 417, 645–649 (2002). https://doi.org/10.1038/nature00779

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