CoChat
Sign Up
Cited by 103Neuroscience and Neuropharmacology ResearchNeural dynamics and brain functionMemory and Neural Mechanisms

Cell-type specific innervation of cortical pyramidal cells at their apical dendrites

Open access
Karimi, Ali, Odenthal, Jan, Drawitsch, Florian, Boergens, Kevin M, Helmstaedter, Moritz·2020·eLife
DOI 10.7554/elife.46876PMC PMC7297530

Published version of a preprint

Open this paper in CoChat — free account

Abstract

We investigated the synaptic innervation of apical dendrites of cortical pyramidal cells in a region between layers (L) 1 and 2 using 3-D electron microscopy applied to four cortical regions in mouse. We found the relative inhibitory input at the apical dendrite’s main bifurcation to be more than 2-fold larger for L2 than L3 and L5 thick-tufted pyramidal cells. Towards the distal tuft dendrites in upper L1, the relative inhibitory input was at least about 2-fold larger for L5 pyramidal cells than for all others. Only L3 pyramidal cells showed homogeneous inhibitory input fraction. The inhibitory-to-excitatory synaptic ratio is thus specific for the types of pyramidal cells. Inhibitory axons preferentially innervated either L2 or L3/5 apical dendrites, but not both. These findings describe connectomic principles for the control of pyramidal cells at their apical dendrites and support differential computational properties of L2, L3 and subtypes of L5 pyramidal cells in cortex.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.7554/elife.46876

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The preference of glutamatergic axons for spines and GABAergic axons for shafts is often misinterpreted as implying that synapses on dendritic shafts are mostly SS.

    “However, this characteristic is often misinterpreted as implying that synapses on dendritic shafts are mostly SS (Motta et al., 2019; Karimi et al., 2020; Loomba et al., 2022).”

    From Unambiguous identification of asymmetric and symmetric synapses using volume electron microscopy (2024) · cites this paper as Karimi et al., 2020

    The Results (‘Shaft vs. spine synapses’; page unavailable) describe spine-preferring axons as putatively excitatory and shaft-preferring axons as putatively inhibitory, but also test for excitatory synapses on shafts. The Results (‘More detailed pyramidal cell type classification’; page unavailable) report that 44% and 60% of shaft synapses onto L5 slender-tufted apical dendrites were likely excitatory in layers 1 and 2, respectively. The paper supports the warning that shaft location does not always establish inhibitory identity, but does not say that the inference is often misinterpreted or establish that shaft synapses generally are not mostly symmetric. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 65 · Cited by 103

Research works printed but not linked: 49

  1. Abs E Poorthuis RB Apelblat D Muhammad K Pardi MB Enke L Kushinsky D Pu DL Eizinger MF Conzelmann KK Spiegel I Letzkus JJ 2018 Learning-Related plasticity in Dendrite-Targeting layer 1 interneurons Neuron 100 684 699 10.1016/j.neuron.2018.09.001 30269988 PMC6226614 · DOI
  2. Bannister NJ Larkman AU 1995 Dendritic morphology of CA1 pyramidal neurones from the rat hippocampus: ii. spine distributions The Journal of Comparative Neurology 360 161 171 10.1002/cne.903600112 7499561 · DOI
  3. Barth AL Poulet JF 2012 Experimental evidence for sparse firing in the neocortex Trends in Neurosciences 35 345 355 10.1016/j.tins.2012.03.008 22579264 · DOI · Paper page
  4. Berning M Boergens KM Helmstaedter M 2015 SegEM: efficient image analysis for High-Resolution connectomics Neuron 87 1193 1206 10.1016/j.neuron.2015.09.003 26402603 · DOI
  5. Boergens KM Berning M Bocklisch T Bräunlein D Drawitsch F Frohnhofen J Herold T Otto P Rzepka N Werkmeister T Werner D Wiese G Wissler H Helmstaedter M 2017 webKnossos: efficient online 3D data annotation for connectomics Nature Methods 14 691 694 10.1038/nmeth.4331 28604722 · DOI
  6. Cheetham CE Barnes SJ Albieri G Knott GW Finnerty GT 2014 Pansynaptic enlargement at adult cortical connections strengthened by experience Cerebral Cortex 24 521 531 10.1093/cercor/bhs334 23118196 PMC3888373 · DOI
  7. Chen JL Villa KL Cha JW So PT Kubota Y Nedivi E 2012 Clustered dynamics of inhibitory synapses and dendritic spines in the adult neocortex Neuron 74 361 373 10.1016/j.neuron.2012.02.030 22542188 PMC3340582 · DOI · Paper page
  8. de Kock CP Sakmann B 2009 Spiking in primary somatosensory cortex during natural whisking in awake head-restrained rats is cell-type specific PNAS 106 16446 16450 10.1073/pnas.0904143106 19805318 PMC2752569 · DOI
  9. de Vivo L Bellesi M Marshall W Bushong EA Ellisman MH Tononi G Cirelli C 2017 Ultrastructural evidence for synaptic scaling across the wake/sleep cycle Science 355 507 510 10.1126/science.aah5982 28154076 PMC5313037 · DOI · Paper page
  10. DeFelipe J Fariñas I 1992 The pyramidal neuron of the cerebral cortex: morphological and chemical characteristics of the synaptic inputs Progress in Neurobiology 39 563 607 10.1016/0301-0082(92)90015-7 1410442 · DOI · Paper page
  11. Drawitsch F Karimi A Boergens KM Helmstaedter M 2018 FluoEM, virtual labeling of axons in three-dimensional electron microscopy data for long-range connectomics eLife 7 e38976 10.7554/eLife.38976 30106377 PMC6158011 · DOI
  12. Franklin K Paxinos G 2008 The Mouse Brain in Stereotaxic Coordinates Academic Press
  13. Gidon A Segev I 2012 Principles governing the operation of synaptic inhibition in dendrites Neuron 75 330 341 10.1016/j.neuron.2012.05.015 22841317 · DOI
  14. Gray EG 1959 Axo-somatic and axo-dendritic synapses of the cerebral cortex: an electron microscope study Journal of Anatomy 93 420 433 13829103 PMC1244535
  15. Groh A Meyer HS Schmidt EF Heintz N Sakmann B Krieger P 2010 Cell-type specific properties of pyramidal neurons in neocortex underlying a layout that is modifiable depending on the cortical area Cerebral Cortex 20 826 836 10.1093/cercor/bhp152 19643810 · DOI
  16. Helmchen F Svoboda K Denk W Tank DW 1999 In vivo dendritic calcium dynamics in deep-layer cortical pyramidal neurons Nature Neuroscience 2 989 996 10.1038/14788 10526338 · DOI
  17. Hua Y Laserstein P Helmstaedter M 2015 Large-volume en-bloc staining for electron microscopy-based connectomics Nature Communications 6 7923 10.1038/ncomms8923 PMC4532871 26235643 · DOI
  18. Hübener M Schwarz C Bolz J 1990 Morphological types of projection neurons in layer 5 of cat visual cortex Journal of Comparative Neurology 301 655 674 10.1002/cne.903010412 2177064 · DOI
  19. Hübener M Bolz J 1988 Morphology of identified projection neurons in layer 5 of rat visual cortex Neuroscience Letters 94 76 81 10.1016/0304-3940(88)90273-X 2468117 · DOI
  20. Iascone DM Li Y Sumbul U Doron M Chen H Andreu V Goudy F Segev I Peng H Polleux F 2018 Whole-neuron synaptic mapping reveals local balance between excitatory and inhibitory synapse organization bioRxiv 10.1101/395384 PMC7244395 32169170 · DOI
  21. Ito M Kato M Kawabata M 1998 Premature bifurcation of the apical dendritic trunk of vibrissa-responding pyramidal neurones of X-irradiated rat neocortex The Journal of Physiology 512 543 553 10.1111/j.1469-7793.1998.543be.x 9763642 PMC2231223 · DOI
  22. Katz Y Menon V Nicholson DA Geinisman Y Kath WL Spruston N 2009 Synapse distribution suggests a two-stage model of dendritic integration in CA1 pyramidal neurons Neuron 63 171 177 10.1016/j.neuron.2009.06.023 19640476 PMC2921807 · DOI
  23. Kolb B Walkey J 1987 Behavioural and anatomical studies of the posterior parietal cortex in the rat Behavioural Brain Research 23 127 145 10.1016/0166-4328(87)90050-7 3566907 · DOI
  24. Kubota Y Hatada S Kondo S Karube F Kawaguchi Y 2007 Neocortical inhibitory terminals innervate dendritic spines targeted by thalamocortical afferents Journal of Neuroscience 27 1139 1150 10.1523/JNEUROSCI.3846-06.2007 17267569 PMC6673192 · DOI
  25. Kubota Y Karube F Nomura M Kawaguchi Y 2016 The diversity of cortical inhibitory synapses Frontiers in Neural Circuits 10 1 15 10.3389/fncir.2016.00027 27199670 PMC4842771 · DOI · Paper page
  26. Larkman A Mason A 1990 Correlations between morphology and electrophysiology of pyramidal neurons in slices of rat visual cortex. I. establishment of cell classes The Journal of Neuroscience 10 1407 1414 10.1523/JNEUROSCI.10-05-01407.1990 2332787 PMC6570081 · DOI
  27. Larkum ME Zhu JJ Sakmann B 1999 A new cellular mechanism for coupling inputs arriving at different cortical layers Nature 398 338 341 10.1038/18686 10192334 · DOI · Paper page
  28. Larkum ME Senn W Lüscher HR 2004 Top-down dendritic input increases the gain of layer 5 pyramidal neurons Cerebral Cortex 14 1059 1070 10.1093/cercor/bhh065 15115747 · DOI · Paper page
  29. Larkum M 2013 A cellular mechanism for cortical associations: an organizing principle for the cerebral cortex Trends in Neurosciences 36 141 151 10.1016/j.tins.2012.11.006 23273272 · DOI · Paper page
  30. Larkum ME Zhu JJ 2002 Signaling of layer 1 and whisker-evoked Ca2+ and na+ action potentials in distal and terminal dendrites of rat neocortical pyramidal neurons in vitro and in vivo The Journal of Neuroscience 22 6991 7005 10.1523/JNEUROSCI.22-16-06991.2002 12177197 PMC6757874 · DOI
  31. Ledergerber D Larkum ME 2012 The time window for generation of dendritic spikes by coincidence of action potentials and EPSPs is layer specific in somatosensory cortex PLOS ONE 7 e33146 10.1371/journal.pone.0033146 22427971 PMC3302831 · DOI
  32. Luo H Hasegawa K Liu M Song WJ 2017 Comparison of the upper marginal neurons of cortical layer 2 with layer 2/3 pyramidal neurons in mouse temporal cortex Frontiers in Neuroanatomy 11 115 10.3389/fnana.2017.00115 29311847 PMC5742574 · DOI
  33. Manns ID Sakmann B Brecht M 2004 Sub- and suprathreshold receptive field properties of pyramidal neurones in layers 5A and 5B of rat somatosensory barrel cortex The Journal of Physiology 556 601 622 10.1113/jphysiol.2003.053132 14724202 PMC1664944 · DOI
  34. Megías M Emri Z Freund TF Gulyás AI 2001 Total number and distribution of inhibitory and excitatory synapses on hippocampal CA1 pyramidal cells Neuroscience 102 527 540 10.1016/S0306-4522(00)00496-6 11226691 · DOI · Paper page
  35. Narayanan RT Egger R Johnson AS Mansvelder HD Sakmann B de Kock CP Oberlaender M 2015 Beyond columnar organization: cell type- and target Layer-Specific principles of horizontal axon projection patterns in rat vibrissal cortex Cerebral Cortex 25 4450 4468 10.1093/cercor/bhv053 25838038 PMC4816792 · DOI
  36. Oláh S Füle M Komlósi G Varga C Báldi R Barzó P Tamás G 2009 Regulation of cortical microcircuits by unitary GABA-mediated volume transmission Nature 461 1278 1281 10.1038/nature08503 19865171 PMC2771344 · DOI · Paper page
  37. Pérez-Garci E Gassmann M Bettler B Larkum ME 2006 The GABAB1b isoform mediates long-lasting inhibition of dendritic Ca2+ spikes in layer 5 somatosensory pyramidal neurons Neuron 50 603 616 10.1016/j.neuron.2006.04.019 16701210 · DOI
  38. Pérez-Garci E Larkum ME Nevian T 2013 Inhibition of dendritic Ca2+ spikes by GABAB receptors in cortical pyramidal neurons is mediated by a direct gi/o-β-subunit interaction with Cav1 channels The Journal of Physiology 591 1599 1612 10.1113/jphysiol.2012.245464 23184512 PMC3624841 · DOI
  39. Rall W 1959 Branching dendritic trees and motoneuron membrane resistivity Experimental Neurology 1 491 527 10.1016/0014-4886(59)90046-9 14435979 · DOI
  40. Rall W Rinzel J 1973 Branch input resistance and steady attenuation for input to one branch of a dendritic neuron model Biophysical Journal 13 648 688 10.1016/S0006-3495(73)86014-X 4715583 PMC1484314 · DOI
  41. Rinzel J Rall W 1974 Transient response in a dendritic neuron model for current injected at one branch Biophysical Journal 14 759 790 10.1016/S0006-3495(74)85948-5 4424185 PMC1334571 · DOI
  42. Scheffer LK Karsh B Vitaladevun S 2013 Automated alignment of imperfect EM images for neural reconstruction arXiv https://arxiv.org/abs/1304.6034 · arXiv
  43. Schmidt H Gour A Straehle J Boergens KM Brecht M Helmstaedter M 2017 Axonal synapse sorting in medial entorhinal cortex Nature 549 469 475 10.1038/nature24005 28959971 · DOI
  44. Staffler B Berning M Boergens KM Gour A Smagt PV Helmstaedter M 2017 SynEM, automated synapse detection for connectomics eLife 6 e26414 10.7554/eLife.26414 28708060 PMC5658066 · DOI
  45. Staiger JF Loucif AJ Schubert D Möck M 2016 Morphological characteristics of electrophysiologically characterized layer vb pyramidal cells in rat barrel cortex PLOS ONE 11 e0164004 10.1371/journal.pone.0164004 27706253 PMC5051735 · DOI
  46. Stuart GJ Sakmann B 1994 Active propagation of somatic action potentials into neocortical pyramidal cell dendrites Nature 367 69 72 10.1038/367069a0 8107777 · DOI · Paper page
  47. Svoboda K Denk W Kleinfeld D Tank DW 1997 In vivo dendritic calcium dynamics in neocortical pyramidal neurons Nature 385 161 165 10.1038/385161a0 8990119 · DOI
  48. Takahashi N Oertner TG Hegemann P Larkum ME 2016 Active cortical dendrites modulate perception Science 354 1587 1590 10.1126/science.aah6066 28008068 · DOI · Paper page
  49. Waters J Larkum M Sakmann B Helmchen F 2003 Supralinear Ca2+ influx into dendritic tufts of layer 2/3 neocortical pyramidal neurons in vitro and in vivo The Journal of Neuroscience 23 8558 8567 13679425 PMC6740370

Authors
Karimi, A., Odenthal, J., Drawitsch, F., Boergens, K. M., & Helmstaedter, M.
Affiliations
Max Planck Institute for Brain Research (DE)
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2020-02-28
Volume
9
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.46876
PMC
PMC7297530
OpenAlex
W3007440872
Cited by
103
References
65
Citations by year
2026: 3 · 2025: 12 · 2024: 14 · 2023: 32 · 2022: 12 · 2021: 16 · 2020: 14
FWCI
8.48
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
Max-Planck-Gesellschaft (Open-access funding)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
cortical pyramidal neurons, apical dendrites, dendritic innervation, inhibitory synaptic input, mouse cortex, connectomics
MeSH terms
Action Potentials, Animals, Axons, Cerebral Cortex, Dendrites, Mice, Inbred C57BL, Synapses, Pyramidal Cells, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review