Abstract

Rodent studies have demonstrated that synaptic dynamics from excitatory to inhibitory neuron types are often dependent on the target cell type. However, these target cell-specific properties have not been well investigated in human cortex, where there are major technical challenges in reliably obtaining healthy tissue, conducting multiple patch-clamp recordings on inhibitory cell types, and identifying those cell types. Here, we take advantage of newly developed methods for human neurosurgical tissue analysis with multiple patch-clamp recordings, post-hoc fluorescent in situ hybridization (FISH), machine learning-based cell type classification and prospective GABAergic AAV-based labeling to investigate synaptic properties between pyramidal neurons and PVALB- vs. SST-positive interneurons. We find that there are robust molecular differences in synapse-associated genes between these neuron types, and that individual presynaptic pyramidal neurons evoke postsynaptic responses with heterogeneous synaptic dynamics in different postsynaptic cell types. Using molecular identification with FISH and classifiers based on transcriptomically identified PVALB neurons analyzed by Patch-seq, we find that PVALB neurons typically show depressing synaptic characteristics, whereas other interneuron types including SST-positive neurons show facilitating characteristics. Together, these data support the existence of target cell-specific synaptic properties in human cortex that are similar to rodent, thereby indicating evolutionary conservation of local circuit connectivity motifs from excitatory to inhibitory neurons and their synaptic dynamics.

Data availability

Single nucleus transcriptomic datasets from human MTG (Hodge et al., 2019) and mouse VISp (Tasic et al., 2018) are available in the Allen Institute website (https://portal.brain-map.org/atlases-and-data/rnaseq). Synaptic connectivity assay datasets including raw traces and related metadata information with MATLAB files (.mat), classifier analysis codes, and their intrinsic membrane property values are available in the DRYAD repository (doi:10.5061/dryad.jdfn2z3dm). Synaptic physiology experimental protocols and related topics are also available in the Allen Institute website (https://portal.brain-map.org/explore/connectivity/synaptic-physiology). To provide more publicly accessible data format, Neurodata Without Borders (NWB) files for synaptic connectivity assay performed in this study and human single cell patch-seq experimental data will be also available soon at DANDI or the BICCN data catalog.

Article and author information

Author details

  1. Mean-Hwan Kim

    Allen Institute for Brain Science, Seattle, United States
    For correspondence
    meanhwank@alleninstitute.org
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8065-4631
  2. Cristina Radaelli

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  3. Elliot R Thomsen

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  4. Deja Monet

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  5. Thomas Chartrand

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7093-8681
  6. Nikolas L Jorstad

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  7. Joseph T Mahoney

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1374-3893
  8. Michael J Taormina

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  9. Brian Long

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  10. Katherine Baker

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  11. Trygve E Bakken

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3373-7386
  12. Luke Campagnola

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  13. Tamara Casper

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  14. Michael Clark

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  15. Nick Dee

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  16. Florence D'Orazi

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  17. Clare Gamlin

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  18. Brian E Kalmbach

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  19. Sara Kebede

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  20. Brian R Lee

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3210-5638
  21. Lindsay Ng

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  22. Jessica Trinh

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  23. Charles Cobbs

    Epilepsy Surgery and Functional Neurosurgery, Swedish Neuroscience Institute, Seattle, United States
    Competing interests
    No competing interests declared.
  24. Ryder P Gwinn

    Epilepsy Surgery and Functional Neurosurgery, Swedish Neuroscience Institute, Seattle, United States
    Competing interests
    No competing interests declared.
  25. C Dirk Keene

    Pathology, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5291-1469
  26. Andrew L Ko

    Department of Neurological Surgery, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  27. Jeffrey G Ojemann

    Department of Neurological Surgery, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  28. Daniel L Silbergeld

    Department of Neurological Surgery, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  29. Staci Sorensen

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  30. Jim Berg

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  31. Kimberly A Smith

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  32. Philip R Nicovich

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  33. Tim Jarsky

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4399-539X
  34. Gabe J Murphy

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  35. Hongkui Zeng

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0326-5878
  36. Jonathan T Ting

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    Jonathan T Ting, U.S. patent application #PCT_US2019_054539 related to this work (vector CN1390)..
  37. Boaz P. Levi

    Allen Institute for Brain Science, Seatlle, United States
    Competing interests
    Boaz P. Levi, U.S. patent application #PCT_US2019_054539 related to this work (vector CN1390)..
  38. Ed Lein

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    Ed Lein, U.S. patent application #PCT_US2019_054539 related to this work (vector CN1390)..

Funding

NIH BRAIN Initiative (1RF1MH114126-01)

  • Jonathan T Ting
  • Boaz P. Levi
  • Ed Lein

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2023, Kim et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Mean-Hwan Kim
  2. Cristina Radaelli
  3. Elliot R Thomsen
  4. Deja Monet
  5. Thomas Chartrand
  6. Nikolas L Jorstad
  7. Joseph T Mahoney
  8. Michael J Taormina
  9. Brian Long
  10. Katherine Baker
  11. Trygve E Bakken
  12. Luke Campagnola
  13. Tamara Casper
  14. Michael Clark
  15. Nick Dee
  16. Florence D'Orazi
  17. Clare Gamlin
  18. Brian E Kalmbach
  19. Sara Kebede
  20. Brian R Lee
  21. Lindsay Ng
  22. Jessica Trinh
  23. Charles Cobbs
  24. Ryder P Gwinn
  25. C Dirk Keene
  26. Andrew L Ko
  27. Jeffrey G Ojemann
  28. Daniel L Silbergeld
  29. Staci Sorensen
  30. Jim Berg
  31. Kimberly A Smith
  32. Philip R Nicovich
  33. Tim Jarsky
  34. Gabe J Murphy
  35. Hongkui Zeng
  36. Jonathan T Ting
  37. Boaz P. Levi
  38. Ed Lein
(2023)
Target cell-specific synaptic dynamics of excitatory to inhibitory neuron connections in supragranular layers of human neocortex
eLife 12:e81863.
https://doi.org/10.7554/eLife.81863

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https://doi.org/10.7554/eLife.81863

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