Article | Published:

Axonal synapse sorting in medial entorhinal cortex

Nature volume 549, pages 469475 (28 September 2017) | Download Citation

Abstract

Research on neuronal connectivity in the cerebral cortex has focused on the existence and strength of synapses between neurons, and their location on the cell bodies and dendrites of postsynaptic neurons. The synaptic architecture of individual presynaptic axonal trees, however, remains largely unknown. Here we used dense reconstructions from three-dimensional electron microscopy in rats to study the synaptic organization of local presynaptic axons in layer 2 of the medial entorhinal cortex, the site of grid-like spatial representations. We observe path-length-dependent axonal synapse sorting, such that axons of excitatory neurons sequentially target inhibitory neurons followed by excitatory neurons. Connectivity analysis revealed a cellular feedforward inhibition circuit involving wide, myelinated inhibitory axons and dendritic synapse clustering. Simulations show that this high-precision circuit can control the propagation of synchronized activity in the medial entorhinal cortex, which is known for temporally precise discharges.

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Acknowledgements

We thank G. Laurent for discussions, A. Borst, A. Motta, R. Rao and A. T. Schaefer for comments on the manuscript, W. Denk for providing the SBEM microtome, Y. Hua for advice on staining protocols, U. Schneeweis for technical help with calbindin staining, M. Berning, E. Klinger and B. Staffler for contributions to data alignment, H. Wissler and D. Rustemovic for tracer management, F. Haake and R. Gebauer for tracing review, E. Eulig, R. Hesse, C. Schramm and M. Zecevic for data curation and J. Abramovich, N. Aydin, N. Berghaus, M. Dell, T. Engelmann, K. Friedl, M. Groothuis, J. Hartel, M.-L. Harwardt, J. Heller, M. Karabel, D. Kurt, E. Laubender, F. Lautenschlager, K. Lust, J. Lösch, L. Matzner, J.-P. Poths, M. Präve, S. Roth, F. Sahin, D. J. Scheliu, N. Schmidt, J. Schmidt-Engler, L. Schütz, S. Sternkopf, A. Strubel, H. Suliman and P. Werner for neuron tracing.

Author information

Affiliations

  1. Department of Connectomics, Max Planck Institute for Brain Research, D-60438 Frankfurt, Germany

    • Helene Schmidt
    • , Anjali Gour
    • , Jakob Straehle
    • , Kevin M. Boergens
    •  & Moritz Helmstaedter
  2. Bernstein Center for Computational Neuroscience, Humboldt University, D-10115 Berlin, Germany

    • Helene Schmidt
    •  & Michael Brecht
  3. NeuroCure Cluster of Excellence, Humboldt University, D-10115 Berlin, Germany

    • Michael Brecht

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Contributions

M.H. and M.B. conceived and supervised the study; H.S. carried out experiments with contributions from A.G.; H.S. analysed the data with contributions from M.H.; K.M.B. contributed to experimental methods; J.S. and M.H. performed circuit modelling; M.H., H.S. and M.B. wrote the paper with contributions from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Helene Schmidt or Moritz Helmstaedter.

Reviewer Information Nature thanks A. Konnerth, M. Witter and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

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  1. 1.

    Reporting Summary

Excel files

  1. 1.

    Supplementary Data 1

    Neuronal adjacency matrix (local connectome) reporting the number of synapses between all reconstructed pre- and postsynaptic processes in P25 and P90 datasets (xls-sheet). See Methods and matlab code in Supplementary Data 2 for analysis of this data.

Text files

  1. 1.

    Supplementary Data 2

    This file contains the matlab code for evaluation of cFFI circuit motifs based on connectivity data reported in Supplementary Data 1 (see Methods for details).

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DOI

https://doi.org/10.1038/nature24005

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