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In vivo reprogramming of circuit connectivity in postmitotic neocortical neurons

Abstract

The molecular mechanisms that control how progenitors generate distinct subtypes of neurons, and how undifferentiated neurons acquire their specific identity during corticogenesis, are increasingly understood. However, whether postmitotic neurons can change their identity at late stages of differentiation remains unknown. To study this question, we developed an electrochemical in vivo gene delivery method to rapidly manipulate gene expression specifically in postmitotic neurons. Using this approach, we found that the molecular identity, morphology, physiology and functional input-output connectivity of layer 4 mouse spiny neurons could be specifically reprogrammed during the first postnatal week by ectopic expression of the layer 5B output neuron–specific transcription factor Fezf2. These findings reveal a high degree of plasticity in the identity of postmitotic neocortical neurons and provide a proof of principle for postnatal re-engineering of specific neural microcircuits in vivo.

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Figure 1: iPo allows rapid delivery of genetic constructs into postmitotic neurons with high spatial precision.
Figure 2: Postnatal expression of Fezf2 in L4 neurons induces cardinal molecular features of L5B output neurons.
Figure 3: Fezf2+ L4 neurons acquire a L5B neuron–like morphology.
Figure 4: Fezf2+ L4 neurons acquire L5B neuron–like output properties.
Figure 5: Fezf2+ L4 neurons acquire L5B-like subcortical inputs.
Figure 6: Fezf2+ L4 neurons acquire L5B-like intracortical inputs.

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Acknowledgements

We thank G. Fishell (New York University) for the gift of the Dlx5/6 plasmid, C.L. Cepko (Harvard University) for the pCAGIG_IRES_GFP and pCAG_ERT2-CRE-ERT2 plasmids, and B. Sauer (US National Institutes of Health) for the pBS302_STOP plasmid, obtained through Addgene. We are thankful to E. Azim and A. Dayer for helpful comments on the manuscript, and to A. Zimmerman and F. Smets for help with the experiments. We thank B. Cerutti for help with the statistical analysis. C.B. is supported by an Ambizione grant from the Swiss National Science Foundation. C.L. is supported by the Swiss National Science Foundation. The Jabaudon laboratory is supported by the Swiss National Science Foundation (PP00P3-123447), the Velux Foundation, the 3R Foundation and the Brain and Behavior Research Foundation. N.T. and J.M. are supported by the Swiss National Science Foundation (PP00A-119026). D.J. and N.T. are supported by a joint Leenaards Foundation for Scientific Research Award.

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D.J. and A.D.l.R. conceived the project and designed the experiments, D.J. and C.B. designed the electrophysiological experiments, and A.D.l.R., C.B., B.G., J.M., N.T. and I.V. performed the experiments. D.J., A.D.l.R., C.B. and C.L. wrote the manuscript.

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Correspondence to Denis Jabaudon.

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The authors declare no competing financial interests.

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De la Rossa, A., Bellone, C., Golding, B. et al. In vivo reprogramming of circuit connectivity in postmitotic neocortical neurons. Nat Neurosci 16, 193–200 (2013). https://doi.org/10.1038/nn.3299

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