Preferential electrical coupling regulates neocortical lineage-dependent microcircuit assembly

Abstract

Radial glial cells are the primary neural progenitor cells in the developing neocortex1. Consecutive asymmetric divisions of individual radial glial progenitor cells produce a number of sister excitatory neurons that migrate along the elongated radial glial fibre, resulting in the formation of ontogenetic columns2,3,4. Moreover, sister excitatory neurons in ontogenetic columns preferentially develop specific chemical synapses with each other rather than with nearby non-siblings5. Although these findings provide crucial insight into the emergence of functional columns in the neocortex, little is known about the basis of this lineage-dependent assembly of excitatory neuron microcircuits at single-cell resolution. Here we show that transient electrical coupling between radially aligned sister excitatory neurons regulates the subsequent formation of specific chemical synapses in the neocortex. Multiple-electrode whole-cell recordings showed that sister excitatory neurons preferentially form strong electrical coupling with each other rather than with adjacent non-sister excitatory neurons during early postnatal stages. This preferential coupling allows selective electrical communication between sister excitatory neurons, promoting their action potential generation and synchronous firing. Interestingly, although this electrical communication largely disappears before the appearance of chemical synapses, blockade of the electrical communication impairs the subsequent formation of specific chemical synapses between sister excitatory neurons in ontogenetic columns. These results suggest a strong link between lineage-dependent transient electrical coupling and the assembly of precise excitatory neuron microcircuits in the neocortex.

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Figure 1: Gap-junction-mediated electrical coupling between sister excitatory neurons in neonatal neocortical ontogenetic columns.
Figure 2: Preferential formation of strong electrical coupling between sister excitatory neurons in neonatal neocortical ontogenetic columns.
Figure 3: Electrical coupling promotes action potential generation and synchronous firing of sister excitatory neurons in neonatal neocortical ontogenetic columns.
Figure 4: Preferential electrical coupling is required for chemical synapse formation between sister excitatory neurons in neocortical ontogenetic columns.

References

  1. 1

    Kriegstein, A. & Alvarez-Buylla, A. The glial nature of embryonic and adult neural stem cells. Annu. Rev. Neurosci. 32, 149–184 (2009)

    CAS  Article  Google Scholar 

  2. 2

    Noctor, S. C., Flint, A. C., Weissman, T. A., Dammerman, R. S. & Kriegstein, A. R. Neurons derived from radial glial cells establish radial units in neocortex. Nature 409, 714–720 (2001)

    ADS  CAS  Article  Google Scholar 

  3. 3

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

    ADS  CAS  Article  Google Scholar 

  4. 4

    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 a recombinant retrovirus. Neuron 1, 635–647 (1988)

    CAS  Article  Google Scholar 

  5. 5

    Yu, Y. C., Bultje, R. S., Wang, X. & Shi, S. H. Specific synapses develop preferentially among sister excitatory neurons in the neocortex. Nature 458, 501–504 (2009)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Peinado, A., Yuste, R. & Katz, L. C. Extensive dye coupling between rat neocortical neurons during the period of circuit formation. Neuron 10, 103–114 (1993)

    CAS  Article  Google Scholar 

  7. 7

    Yuste, R., Peinado, A. & Katz, L. C. Neuronal domains in developing neocortex. Science 257, 665–669 (1992)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Yuste, R., Nelson, D. A., Rubin, W. W. & Katz, L. C. Neuronal domains in developing neocortex: mechanisms of coactivation. Neuron 14, 7–17 (1995)

    CAS  Article  Google Scholar 

  9. 9

    Willecke, K. et al. Structural and functional diversity of connexin genes in the mouse and human genome. Biol. Chem. 383, 725–737 (2002)

    CAS  Article  Google Scholar 

  10. 10

    Elias, L. A., Wang, D. D. & Kriegstein, A. R. Gap junction adhesion is necessary for radial migration in the neocortex. Nature 448, 901–907 (2007)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Nadarajah, B., Jones, A. M., Evans, W. H. & Parnavelas, J. G. Differential expression of connexins during neocortical development and neuronal circuit formation. J. Neurosci. 17, 3096–3111 (1997)

    CAS  Article  Google Scholar 

  12. 12

    Connors, B. W. & Long, M. A. Electrical synapses in the mammalian brain. Annu. Rev. Neurosci. 27, 393–418 (2004)

    CAS  Article  Google Scholar 

  13. 13

    Bennett, M. V. & Zukin, R. S. Electrical coupling and neuronal synchronization in the mammalian brain. Neuron 41, 495–511 (2004)

    CAS  Article  Google Scholar 

  14. 14

    Lo Turco, J. J. & Kriegstein, A. R. Clusters of coupled neuroblasts in embryonic neocortex. Science 252, 563–566 (1991)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Connors, B. W., Benardo, L. S. & Prince, D. A. Coupling between neurons of the developing rat neocortex. J. Neurosci. 3, 773–782 (1983)

    CAS  Article  Google Scholar 

  16. 16

    Gibson, J. R., Beierlein, M. & Connors, B. W. Two networks of electrically coupled inhibitory neurons in neocortex. Nature 402, 75–79 (1999)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Galarreta, M. & Hestrin, S. A network of fast-spiking cells in the neocortex connected by electrical synapses. Nature 402, 72–75 (1999)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Wang, Y., Barakat, A. & Zhou, H. Electrotonic coupling between pyramidal neurons in the neocortex. PLoS ONE 5, e10253 (2010)

    ADS  Article  Google Scholar 

  19. 19

    Pangratz-Fuehrer, S. & Hestrin, S. Synaptogenesis of electrical and GABAergic synapses of fast-spiking inhibitory neurons in the neocortex. J. Neurosci. 31, 10767–10775 (2011)

    CAS  Article  Google Scholar 

  20. 20

    Stevens, C. F. & Zador, A. M. Input synchrony and the irregular firing of cortical neurons. Nature Neurosci. 1, 210–217 (1998)

    CAS  Article  Google Scholar 

  21. 21

    Hebb, D. O. The Organization of Behavior (Wiley, 1949)

    Google Scholar 

  22. 22

    Katz, L. C. & Shatz, C. J. Synaptic activity and the construction of cortical circuits. Science 274, 1133–1138 (1996)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Beahm, D. L. et al. Mutation of a conserved threonine in the third transmembrane helix of α- and β-connexins creates a dominant-negative closed gap junction channel. J. Biol. Chem. 281, 7994–8009 (2006)

    CAS  Article  Google Scholar 

  24. 24

    Rouan, F. et al. Trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation. J. Cell Sci. 114, 2105–2113 (2001)

    CAS  PubMed  Google Scholar 

  25. 25

    Personius, K. E. & Balice-Gordon, R. J. Loss of correlated motor neuron activity during synaptic competition at developing neuromuscular synapses. Neuron 31, 395–408 (2001)

    CAS  Article  Google Scholar 

  26. 26

    Chuang, C. F., Vanhoven, M. K., Fetter, R. D., Verselis, V. K. & Bargmann, C. I. An innexin-dependent cell network establishes left–right neuronal asymmetry in C. elegans. Cell 129, 787–799 (2007)

    CAS  Article  Google Scholar 

  27. 27

    Curtin, K. D., Zhang, Z. & Wyman, R. J. Gap junction proteins expressed during development are required for adult neural function in the Drosophila optic lamina. J. Neurosci. 22, 7088–7096 (2002)

    CAS  Article  Google Scholar 

  28. 28

    Dupont, E., Hanganu, I. L., Kilb, W., Hirsch, S. & Luhmann, H. J. Rapid developmental switch in the mechanisms driving early cortical columnar networks. Nature 439, 79–83 (2006)

    ADS  CAS  Article  Google Scholar 

  29. 29

    Kandler, K. & Katz, L. C. Coordination of neuronal activity in developing visual cortex by gap junction-mediated biochemical communication. J. Neurosci. 18, 1419–1427 (1998)

    CAS  Article  Google Scholar 

  30. 30

    Du, Z. et al. Introduction of oncogenes into mammary glands in vivo with an avian retroviral vector initiates and promotes carcinogenesis in mouse models. Proc. Natl Acad. Sci. USA 103, 17396–17401 (2006)

    ADS  CAS  Article  Google Scholar 

  31. 31

    Holland, E. C., Hively, W. P., DePinho, R. A. & Varmus, H. E. A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Dev. 12, 3675–3685 (1998)

    CAS  Article  Google Scholar 

  32. 32

    Neyton, J. & Trautmann, A. Single-channel currents of an intercellular junction. Nature 317, 331–335 (1985)

    ADS  CAS  Article  Google Scholar 

  33. 33

    Vos, B. P., Maex, R., Volny-Luraghi, A. & De Schutter, E. Parallel fibers synchronize spontaneous activity in cerebellar Golgi cells. J. Neurosci. 19, RC6 (1999)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank the following: C. I. Bargmann, Y. Dan, A. L. Joyner, K. M. Hively and Y. Chin for comments on the manuscript; F. H. Gage for the 293gp NIT–GFP package cell line; E. C. Holland for nestin-TVA transgenic mice; and members of the Shi and Yu laboratories for their input. This work was supported by grants from the Ministry of Science and Technology of China (2012CB966300), the Natural Science Foundation of China (31121061 and 31070947), the Pujiang Talent Project of the Shanghai Science and Technology Committee (10PJ1400700), the Foundation of the Ministry of Education of China (20100071120061) (Y.-C.Y.), the National Institutes of Health (R01DA024681 and R21NS072483 (S.-H.S.), R21MH083624 (S.-H.S. and K.H.) and R01GM065947 (G.E.S.)), the McKnight Foundation and the March of Dimes Foundation (S.-H.S.).

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Y.-C.Y., S.H. and S.-H.S. conceived the project. Y.-C.Y. and S.H. conducted the electrophysiology and morphology reconstruction experiments. S.C., Y.F. and K.N.B. generated viruses and performed in utero virus injections and morphological reconstructions. X.-H.Y., J.M. and K.P.G. performed immunohistochemistry and morphological reconstruction experiments. G.E.S. helped with CX26-carrying retrovirus engineering. K.H. performed cross-correlogram analysis. Y.-C.Y., S. H. and S.-H.S. analysed the data, interpreted the results and wrote the manuscript. All authors edited the manuscript.

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Correspondence to Yong-Chun Yu or Shuijin He or Song-Hai Shi.

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This file contains Supplementary Figures 1-8. (PDF 3136 kb)

Supplementary Movie 1

In this movie file we see the localization of Cx26 puncta (red) at the dendrosomatic contacts of sister excitatory neurons in ontogenetic columns expressing EGFP (green). The three-dimensional image was reconstructed using Imaris and the play rate is 25 frames per second. (MOV 5407 kb)

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Yu, Y., He, S., Chen, S. et al. Preferential electrical coupling regulates neocortical lineage-dependent microcircuit assembly. Nature 486, 113–117 (2012). https://doi.org/10.1038/nature10958

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