Signature morphoelectric properties of diverse GABAergic interneurons in the human neocortex

Brian R. Lee, Rachel Dalley, Jeremy A. Miller, Thomas Chartrand, Jennie Close, Rusty Mann, Alice Mukora, Lindsay Ng, Lauren Alfiler, Katherine Baker, Darren Bertagnolli, Krissy Brouner, Tamara Casper, Eva Csajbok, Nicholas Donadio, Stan L.W. Driessens, Tom Egdorf, Rachel Enstrom, Anna A. Galakhova, Amanda GaryEmily Gelfand, Jeff Goldy, Kristen Hadley, Tim S. Heistek, Dijon Hill, Wen Hsien Hou, Nelson Johansen, Nik Jorstad, Lisa Kim, Agnes Katalin Kocsis, Lauren Kruse, Michael Kunst, Gabriela León, Brian Long, Matthew Mallory, Michelle Maxwell, Medea McGraw, Delissa McMillen, Erica J. Melief, Gabor Molnar, Marty T. Mortrud, Dakota Newman, Julie Nyhus, Ximena Opitz-Araya, Attila Ozsvár, Trangthanh Pham, Alice Pom, Lydia Potekhina, Ram Rajanbabu, Augustin Ruiz, Susan M. Sunkin, Ildikó Szöts, Naz Taskin, Bargavi Thyagarajan, Michael Tieu, Jessica Trinh, Sara Vargas, David Vumbaco, Femke Waleboer, Sarah Walling-Bell, Natalie Weed, Grace Williams, Julia Wilson, Shenqin Yao, Thomas Zhou, Pál Barzó, Trygve Bakken, Charles Cobbs, Nick Dee, Richard G. Ellenbogen, Luke Esposito, Manuel Ferreira, Nathan W. Gouwens, Benjamin Grannan, Ryder P. Gwinn, Jason S. Hauptman, Rebecca Hodge, Tim Jarsky, C. Dirk Keene, Andrew L. Ko, Anders Rosendal Korshoej, Boaz P. Levi, Kaare Meier, Jeffrey G. Ojemann, Anoop Patel, Jacob Ruzevick, Daniel L. Silbergeld, Kimberly Smith, Jens Christian Sørensen, Jack Waters, Hongkui Zeng, Jim Berg, Marco Capogna, Natalia A. Goriounova, Brian Kalmbach, Christiaan P.J. de Kock, Huib D. Mansvelder, Staci A. Sorensen, Gabor Tamas, Ed S. Lein, Jonathan T. Ting

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Abstract

Human cortex transcriptomic studies have revealed a hierarchical organization of γ-aminobutyric acid-producing (GABAergic) neurons from subclasses to a high diversity of more granular types. Rapid GABAergic neuron viral genetic labeling plus Patch-seq (patch-clamp electrophysiology plus single-cell RNA sequencing) sampling in human brain slices was used to reliably target and analyze GABAergic neuron subclasses and individual transcriptomic types. This characterization elucidated transitions between PVALB and SST subclasses, revealed morphological heterogeneity within an abundant transcriptomic type, identified multiple spatially distinct types of the primate-specialized double bouquet cells (DBCs), and shed light on cellular differences between homologous mouse and human neocortical GABAergic neuron types. These results highlight the importance of multimodal phenotypic characterization for refinement of emerging transcriptomic cell type taxonomies and for understanding conserved and specialized cellular properties of human brain cell types.

Original languageEnglish
Article numbereadf6484
Pages (from-to)1-16
Number of pages17
JournalScience (New York, N.Y.)
Volume382
Issue number6667
Early online date13 Oct 2023
DOIs
Publication statusPublished - Oct 2023

Funding

We thank the Allen Institute founder, P. G. Allen, for his vision, encouragement, and support. We additionally acknowledge support and input from our remaining U01 BRAIN grant consortium colleagues as well as various Allen Institute teams including Tissue Procurement and Tissue Processing, Viral Technology, Neuroanatomy, Histology and Reagent Prep, Imaging, Rseq core, Molecular Genetics, Program Management, Human Cell Types, In Vitro Single Cell Characterization, Data and Technology, Engineering, Transcriptomics, and Genomics. We also thank our Seattle-, Amsterdam-, and Szeged-area hospital partners for support and assistance with neurosurgical tissue procurement. This publication was supported by and coordinated through the BICCN. This publication is part of the Human Cell Atlas (www.humancellatlas.org/publications/). The research reported in this publication was supported by the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH) BRAIN Initiative awards 1RF1MH114126 and UG3MH120095 (J.T.T., B.P.L., and E.S.L.), BRAIN Initiative Cell Census Network award U01MH114812 (E.S.L., H.D.M., and G.T.), and by NIMH of the NIH award 1RF1MH128778 (S.A.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was also supported in part by The Nancy and Buster Alvord Endowment (C.D.K.); grant 945539 (Human Brain Project SGA3) from the European Union’s Horizon 2020 Framework Programme for Research and Innovation (H.D.M.); European Research Council advanced grant “fasthumanneuron” 101093198 (H.D.M.); the Dutch Research Council (NWO) Open Competition (ENW-M2) grant OCENW. M20.285 (C.P.J.d.K.); the NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012); VI.Vidi.213.014 grant from the Dutch Research Council (N.A.G.); the Danish Cancer Society grants R304-A17698-B5570 and R295-A16770 (A.R.K.); The Lundbeck Foundation grant R325-2019-1490 (A.R.K. and A.O.); the Independent Research Fund Denmark grants 9039-00307B (A.R.K.) and DFF-37741 (W.H.H.); and National Research, Development, and Innovation Office grants KKP 133807 Élvonal, ÚNKP-20-5-SZTE-681, TKP2021-EGA-09, TKP-2021-EGA-28, and 2019-2.1.7-ERA-NET-2022-00038; and Eötvös Loránd Research Network grants ELKH-SZTE Agykérgi Neuronhálózatok Kutatócsoport and KÖ-36/2021 (G.T.).

FundersFunder number
ELKH-SZTE Agykérgi Neuronhálózatok KutatócsoportKÖ-36/2021
ENW-M2024.004.012
European Union’s Horizon 2020 Framework Programme for Research and Innovation
National Institutes of HealthUG3MH120095, U01MH114812, 1RF1MH114126, 1RF1MH128778
National Institute of Mental Health
Nancy and Buster Alvord Endowment945539
Kræftens BekæmpelseR295-A16770, R304-A17698-B5570
Allen Institute
European Research Council101093198
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Lundbeck FoundationR325-2019-1490
Danmarks Frie ForskningsfondDFF-37741, 9039-00307B
National Research, Development and Innovation Office2019-2.1.7-ERA-NET-2022-00038, KKP 133807, TKP-2021-EGA-28, ÚNKP-20-5-SZTE-681, TKP2021-EGA-09

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