Article | Published:

Transplanted embryonic neurons integrate into adult neocortical circuits

Nature volume 539, pages 248253 (10 November 2016) | Download Citation

  • An Erratum to this article was published on 07 December 2016

This article has been updated

Abstract

The ability of the adult mammalian brain to compensate for neuronal loss caused by injury or disease is very limited. Transplantation aims to replace lost neurons, but the extent to which new neurons can integrate into existing circuits is unknown. Here, using chronic in vivo two-photon imaging, we show that embryonic neurons transplanted into the visual cortex of adult mice mature into bona fide pyramidal cells with selective pruning of basal dendrites, achieving adult-like densities of dendritic spines and axonal boutons within 4–8 weeks. Monosynaptic tracing experiments reveal that grafted neurons receive area-specific, afferent inputs matching those of pyramidal neurons in the normal visual cortex, including topographically organized geniculo-cortical connections. Furthermore, stimulus-selective responses refine over the course of many weeks and finally become indistinguishable from those of host neurons. Thus, grafted neurons can integrate with great specificity into neocortical circuits that normally never incorporate new neurons in the adult brain.

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Change history

  • 09 November 2016

    Minor changes were made to Figs 4, 5 and Extended Data Fig. 8.

  • 17 November 2016

    The resolution of Fig. 4 was increased.

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Acknowledgements

We thank D. Franzen, G. Jäger, T. Simon, V. Staiger, H. Tultschin and F. Voss for technical support, and A. Lepier for viral vector expertise. M. Sperling, P. Goltstein and A. Grade helped with hardware and software. This work was supported by the German Research Foundation (SFB 870 ‘Neuronal Circuits’: M.G., L.D., K.-K.C., T.B. and M.H.; SPP 1757: M.G. and L.D.), the Advanced ERC grant ChroNeuroRepair (M.G.), the Helmholtz Alliance Icemed (M.G.), the Boehringer Ingelheim Fonds (S.F.), and the Max Planck Society (S.F., T.B. and M.H.).

Author information

Author notes

    • Susanne Falkner
    •  & Sofia Grade

    These authors contributed equally to this work.

    • Magdalena Götz
    •  & Mark Hübener

    These authors jointly supervised this work.

Affiliations

  1. Max Planck Institute of Neurobiology, D-82152 Martinsried, Germany

    • Susanne Falkner
    • , Tobias Bonhoeffer
    •  & Mark Hübener
  2. Physiological Genomics, Biomedical Center, Ludwig-Maximilians University Munich, D-82152 Planegg, Germany

    • Sofia Grade
    • , Leda Dimou
    •  & Magdalena Götz
  3. Institute of Stem Cell Research, Helmholtz Center Munich, German Research Center for Environmental Health, D-85764 Neuherberg, Germany

    • Sofia Grade
    • , Leda Dimou
    •  & Magdalena Götz
  4. SYNERGY, Excellence Cluster of Systems Neurology, Biomedical Center, Ludwig-Maximilians University Munich, D-82152 Planegg , Germany

    • Leda Dimou
    •  & Magdalena Götz
  5. Max von Pettenkofer Institute and Gene Center, Ludwig-Maximilians University Munich, D-81377 Munich, Germany

    • Karl-Klaus Conzelmann

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Contributions

The original idea for the study came from M.G. M.G, M.H. and T.B. then initiated the study and planned the experimental approach. S.F., S.G., M.G., M.H. and L.D. designed the experiments; S.F. performed in vivo imaging experiments and analysis; S.G. performed the experiments in fixed tissue including connectivity experiments and analysis. M.G. and L.D. provided the lesion model. K.-K.C. provided the rabies virus and expertise for its use for monosynaptic tracing. Finally, M.G., M.H., S.G. and S.F. wrote the paper with input from T.B., L.D. and K.-K.C.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Magdalena Götz or Mark Hübener.

Extended data

Supplementary information

Videos

  1. 1.

    Morphological development of a transplanted neuron

    Neuron 3 to 92 dpt (same as in Fig. 1), developing a L2/3 pyramidal cell-like morphology within 3 wpt. Stable overall morphology 4 to 13 wpt. In vivo two-photon z-stacks depicted as maximum projections, time series.

  2. 2.

    Formation of dendritic spines

    Dendrite 6 to 75 dpt, forming first dendritic spines at 9 dpt. Z-stack maximum projections, time series.

  3. 3.

    Formation of axonal boutons

    Axon 5 to 84 dpt (same as in Fig. 2), forming first axonal boutons at 5 dpt, a secondary branch forms at 7 dpt. Z-stack maximum projections, time series.

  4. 4.

    3D reconstruction of dLGN relay cells retrogradely traced in mice with distinct transplantation sites in V1

    Data from each mouse (n=8) is represented with a distinct color, and each sphere corresponds to one neuron (n=3-96/mouse). Animation starts with an anterior view and then rotates around several axes, demonstrating that cells form segregated clusters in specific parts of the dLGN (surface in wireframe; see Extended Data Fig. 8c).

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DOI

https://doi.org/10.1038/nature20113

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