Human cortical expansion involves diversification and specialization of supragranular intratelencephalic-projecting neurons
Authors: Berg Jim , Sorensen Staci A. , Ting Jonathan T. , Miller Jeremy A. , Chartrand Thomas , Buchin Anatoly , Bakken Trygve E. , Budzillo Agata , Dee Nick , Ding Song-Lin , Gouwens Nathan W. , Hodge Rebecca D. , Kalmbach Brian , Lee Changkyu , Lee Brian R. , Alfiler Lauren , Baker Katherine , Barkan Eliza , Beller Allison , Berry Kyla , Bertagnolli Darren , Bickley Kris , Bomben Jasmine , Braun Thomas , Brouner Krissy , Casper Tamara , Chong Peter , Crichton Kirsten , Dalley Rachel , de Frates Rebecca , Desta Tsega , Dingman Lee Samuel , D’Orazi Florence , Dotson Nadezhda , Egdorf Tom , Enstrom Rachel , Farrell Colin , Feng David , Fong Olivia , Furdan Szabina , Galakhova Anna A. , Gamlin Clare , Gary Amanda , Glandon Alexandra , Goldy Jeff , Gorham Melissa , Goriounova Natalia A. , Gratiy Sergey , Graybuck Lucas , Gu Hong , Hadley Kristen , Hansen Nathan , Heistek Tim S. , Henry Alex M. , Heyer Djai B. , Hill DiJon , Hill Chris , Hupp Madie , Jarsky Tim , Kebede Sara , Keene Lisa , Kim Lisa , Kim Mean-Hwan , Kroll Matthew , Latimer Caitlin , Levi Boaz P. , Link Katherine E. , Mallory Matthew , Mann Rusty , Marshall Desiree , Maxwell Michelle , McGraw Medea , McMillen Delissa , Melief Erica , Mertens Eline J. , Mezei Leona , Mihut Norbert , Mok Stephanie , Molnar Gabor , Mukora Alice , Ng Lindsay , Ngo Kiet , Nicovich Philip R. , Nyhus Julie , Olah Gaspar , Oldre Aaron , Omstead Victoria , Ozsvar Attila , Park Daniel , Peng Hanchuan , Pham Trangthanh , Pom Christina A. , Potekhina Lydia , Rajanbabu Ramkumar , Ransford Shea , Reid David , Rimorin Christine , Ruiz Augustin , Sandman David , Sulc Josef , Sunkin Susan M. , Szafer Aaron , Szemenyei Viktor , Thomsen Elliot R. , Tieu Michael , Torkelson Amy , Trinh Jessica , Tung Herman , Wakeman Wayne , Ward Katelyn , Wilbers René , Williams Grace , Yao Zizhen , Yoon Jae-Geun , Anastassiou Costas , Arkhipov Anton , Barzo Pal , Bernard Amy , Cobbs Charles , de Witt Hamer Philip C. , Ellenbogen Richard G. , Esposito Luke , Ferreira Manuel , Gwinn Ryder P. , Hawrylycz Michael J. , Hof Patrick R. , Idema Sander , Jones Allan R. , Keene C.Dirk , Ko Andrew L. , Murphy Gabe J. , Ng Lydia , Ojemann Jeffrey G. , Patel Anoop P. , Phillips John W. , Silbergeld Daniel L. , Smith Kimberly , Tasic Bosiljka , Yuste Rafael , Segev Idan , de Kock Christiaan P.J. , Mansvelder Huibert D. , Tamas Gabor , Zeng Hongkui , Koch Christof , Lein Ed S. 
Published: April 2020

The neocortex is disproportionately expanded in human compared to mouse, both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers that selectively make connections within the cortex and other telencephalic structures. Single-cell transcriptomic analyses of human and mouse cortex show an increased diversity of glutamatergic neuron types in supragranular cortex in human and pronounced gradients as a function of cortical depth. To probe the functional and anatomical correlates of this transcriptomic diversity, we describe a robust Patch-seq platform using neurosurgically-resected human tissues. We characterize the morphological and physiological properties of five transcriptomically defined human glutamatergic supragranular neuron types. Three of these types have properties that are specialized compared to the more homogeneous properties of transcriptomically defined homologous mouse neuron types. The two remaining supragranular neuron types, located exclusively in deep layer 3, do not have clear mouse homologues in supragranular cortex but are transcriptionally most similar to deep layer mouse intratelencephalic-projecting neuron types. Furthermore, we reveal the transcriptomic types in deep layer 3 that express high levels of non-phosphorylated heavy chain neurofilament protein that label long-range neurons known to be selectively depleted in Alzheimer’s disease. Together, these results demonstrate the power of transcriptomic cell type classification, provide a mechanistic underpinning for increased complexity of cortical function in human cortical evolution, and implicate discrete transcriptomic cell types as selectively vulnerable in disease.