Skip to main content
SpringerLink
Log in

Bi-directional Control of Synaptic Input Summation and Spike Generation by GABAergic Inputs at the Axon Initial Segment

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Differing from other subtypes of inhibitory interneuron, chandelier or axo-axonic cells form depolarizing GABAergic synapses exclusively onto the axon initial segment (AIS) of targeted pyramidal cells (PCs). However, the debate whether these AIS-GABAergic inputs produce excitation or inhibition in neuronal processing is not resolved. Using realistic NEURON modeling and electrophysiological recording of cortical layer-5 PCs, we quantitatively demonstrate that the onset-timing of AIS-GABAergic input, relative to dendritic excitatory glutamatergic inputs, determines its bi-directional regulation of the efficacy of synaptic integration and spike generation in a PC. More specifically, AIS-GABAergic inputs promote the boosting effect of voltage-activated Na+ channels on summed synaptic excitation when they precede glutamatergic inputs by >15 ms, while for nearly concurrent excitatory inputs, they primarily produce a shunting inhibition at the AIS. Thus, our findings offer an integrative mechanism by which AIS-targeting interneurons exert sophisticated regulation of the input-output function in targeted PCs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Jones EG. Varieties and distribution of non-pyramidal cells in the somatic sensory cortex of the squirrel monkey. J Comp Neurol 1975, 160: 205–267.

    Article  CAS  Google Scholar 

  2. Szentágothai J. The ‘module-concept’ in cerebral cortex architecture. Brain Res 1975, 95: 475–496.

    Article  Google Scholar 

  3. Somogyi P. A specific ‘axo-axonal’ interneuron in the visual cortex of the rat. Brain Res 1977, 136: 345–350.

    Article  CAS  Google Scholar 

  4. Howard A, Tamas G, Soltesz I. Lighting the chandelier: New vistas for axo-axonic cells. Trends Neurosci 2005, 28: 310–316.

    Article  CAS  Google Scholar 

  5. Fairén A, Valverde F. A specialized type of neuron in the visual cortex of cat: A Golgi and electron microscope study of chandelier cells. J Comp Neurol 1980, 194: 761–779.

    Article  Google Scholar 

  6. Inda MC, DeFelipe J, Muñoz A. Voltage-gated ion channels in the axon initial segment of human cortical pyramidal cells and their relationship with chandelier cells. Proc Natl Acad Sci U S A 2006, 103: 2920–2925.

    Article  CAS  Google Scholar 

  7. Palmer LM, Stuart GJ. Site of action potential initiation in layer 5 pyramidal neurons. J Neurosci 2006, 26: 1854–1863.

    Article  CAS  Google Scholar 

  8. Kole MHP, Stuart GJ. Is action potential threshold lowest in the axon? Nat Neurosci 2008, 11: 1253–1255.

    Article  CAS  Google Scholar 

  9. Kole MHP, Ilschner SU, Kampa BM, Williams SR, Ruben PC, Stuart GJ. Action potential generation requires a high sodium channel density in the axon initial segment. Nat Neurosci 2008, 11: 178–186.

    Article  CAS  Google Scholar 

  10. Hu W, Tian C, Li T, Yang M, Hou H, Shu Y. Distinct contributions of Nav1.6 and Nav1.2 in action potential initiation and backpropagation. Nat Neurosci 2009, 12: 996–1002.

    Article  CAS  Google Scholar 

  11. Szabadics J, Varga C, Molnár G, Oláh S, Barzó P, Tamás G. Excitatory effect of GABAergic axo-axonic cells in cortical microcircuits. Science 2006, 311: 233–235.

    Article  CAS  Google Scholar 

  12. Khirug S, Yamada J, Afzalov R, Voipio J, Khiroug L, Kai K. GABAergic depolarization of the axon initial segment in cortical principal neurons is caused by the Na-K-2Cl cotransporter NKCC1. J Neurosci 2008, 28: 4635–4639.

    Article  CAS  Google Scholar 

  13. Woodruff A, Xu Q, Anderson SA, Yuste R. Depolarizing effect of neocortical chandelier neurons. Front Neural Circuits 2009, 3: 15.

    Article  Google Scholar 

  14. Glickfeld LL, Roberts JD, Somogyi P, Scanziani M. Interneurons hyperpolarize pyramidal cells along their entire somatodendritic axis. Nat Neurosci 2009, 12: 21–23.

    Article  CAS  Google Scholar 

  15. Ben-Ari Y, Gaiarsa JL, Tyzio R, Khazipov R. GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol Rev 2007, 87: 1215–1284.

    Article  CAS  Google Scholar 

  16. Xu C, Zhao MX, Poo MM, Zhang XH. GABAB receptor activation mediates frequency-dependent plasticity of developing GABAergic synapses. Nat Neurosci 2008, 11: 1410–1418.

    Article  CAS  Google Scholar 

  17. Woodruff AR, Monyer H, Sah P. GABAergic excitation in the basolateral amygdala. J Neurosci 2006, 26: 11881–11887.

    Article  CAS  Google Scholar 

  18. Molnár G, Oláh S, Komlósi G, Füle M, Szabadics J, Varga C. Complex events initiated by individual spikes in the human cerebral cortex. PLoS Biol 2008, 6: e222.

    Article  Google Scholar 

  19. Woodruff AR, McGarry LM, Vogels TP, Inan M, Anderson SA, Yuste R. State-dependent function of neocortical chandelier cells. J Neurosci 2011, 31: 17872–17886.

    Article  CAS  Google Scholar 

  20. Rall W. Neural Theory and Modeling, ed R, Stanford University Press, Reiss Stanford, 1964, pp 73–97.

    Google Scholar 

  21. Cash S, Yuste R. Linear summation of excitatory inputs by CA1 pyramidal neurons. Neuron 1999, 22: 383–394.

    Article  CAS  Google Scholar 

  22. Poirazi P, Brannon T, Mel BW. Arithmetic of subthreshold synaptic summation in a model CA1 pyramidal cell. Neuron 2003, 37: 977–987.

    Article  CAS  Google Scholar 

  23. Poirazi P, Brannon T, Mel BW. Pyramidal neuron as two-layer neural network. Neuron 2003, 37: 989–999.

    Article  CAS  Google Scholar 

  24. Polsky A, Mel BW, Schiller J. Computational subunits in thin dendrites of pyramidal cells. Nat Neurosci 2004, 7: 621–627.

    Article  CAS  Google Scholar 

  25. Losonczy A, Magee JC. Integrative properties of radial oblique dendrites in hippocampal CA1 pyramidal neurons. Neuron 2006, 50: 291–307.

    Article  CAS  Google Scholar 

  26. Eccles, J. The nature of cortical inhibition. Proc R Soc London Ser B 1961: 445–476.

  27. Blomfield S. Arithmetical operations performed by nerve cells. Brain Res 1974, 69: 115–124.

    Article  CAS  Google Scholar 

  28. Fatt P, Katz B. The effect of inhibitory nerve impulses on a crustacean muscle fibre. J Physiol 1953, 121: 374–389.

    Article  CAS  Google Scholar 

  29. Koch C, Poggio T, Torre V. Nonlinear interactions in a dendritic tree: Localization, timing, and role in information processing. Proc Natl Acad Sci U S A 1983, 80: 2799–2802.

    Article  CAS  Google Scholar 

  30. Koch C. Biophysics of Computation. Oxford University Press, New York, 1999.

    Google Scholar 

  31. Hao J, Wang X, Dan Y, Poo MM, Zhang XH. An arithmetic rule for spatial summation of excitatory and inhibitory inputs in pyramidal neurons. Proc Natl Acad Sci U S A 2009, 106: 21906–21911.

    Article  CAS  Google Scholar 

  32. Zhou D, Li ST, Zhang XH, Cai D. Phenomenological incorporation of nonlinear dendritic integration using integrate-and-fire neuronal frameworks. PLoS One 2013, 8: e53508.

    Article  CAS  Google Scholar 

  33. Li S, Liu N, Zhang XH, Zhou D, Cai D. Bilinearity in spatiotemporal integration of synaptic inputs. PLoS Comput Biol 2014, 10: e1004014.

    Article  Google Scholar 

  34. Li ST, Liu N, Yao L, Zhang XH, Zhou D, Cai D. Determination of effective synaptic conductances using somatic voltage clamp. PLoS Comput Biol 2019, 15: e1006871.

    Article  Google Scholar 

  35. Hines ML, Carnevale NT. The NEURON simulation environment. Neural Comput 1997, 9: 1179–1209.

    Article  CAS  Google Scholar 

  36. Carnevale N, Hines M (2006) The NEURON Book. Cambridge University Press, Cambridge.

    Book  Google Scholar 

  37. He LJ, Liu N, Cheng TL, Chen XJ, Li Y, Shu YS, et al. Conditional deletion of Mecp2 in parvalbumin-expressing GABAergic cells results in the absence of critical period plasticity. Nat Commun 2014, 5: 5036.

    Article  CAS  Google Scholar 

  38. Tamás G, Szabadics J. Summation of unitary IPSPs elicited by identified axo-axonic interneurons. Cereb Cortex 2004, 14: 823–826.

    Article  Google Scholar 

  39. Wang X, Hooks BM, Sun Q. Thorough GABAergic innervation of the entire axon initial segment revealed by an optogenetic ‘laserspritzer.’ J Physiol 2014, 592: 4257–4276.

    Article  CAS  Google Scholar 

  40. Hu W, Shu YS. Axonal bleb recording. Neurosci Bull 2012, 28: 342–350.

    Article  Google Scholar 

  41. Stuart G, Sakmann B. Amplification of EPSPs by axosomatic sodium channels in neocortical pyramidal neurons. Neuron 1995, 15: 1065–1076.

    Article  CAS  Google Scholar 

  42. González-Burgos G, Barrionuevo G. Voltage-gated sodium channels shape subthreshold EPSPs in layer 5 pyramidal neurons from rat prefrontal cortex. J Neurophysiol 2001, 86: 1671–1684.

    Article  Google Scholar 

  43. Destexhe A, Rudolph M, Paré D. The high-conductance state of neocortical neurons in vivo. Nat Rev Neurosci 2003, 4: 739–751.

    Article  CAS  Google Scholar 

  44. Schwindt P, Crill W. Equivalence of amplified current flowing from dendrite to soma measured by alteration of repetitive firing and by voltage clamp in layer 5 pyramidal neurons. J Neurophysiol 1996, 76: 3731–3739.

    Article  CAS  Google Scholar 

  45. Lipowsky R, Gillessen T, Alzheimer C. Dendritic Na+ channels amplify EPSPs in hippocampal CA1 pyramidal cells. J Neurophysiol 1996, 76: 2181–2191.

    Article  CAS  Google Scholar 

  46. Johnston D, Magee JC, Colbert CM, Christie BR. Active properties of neuronal dendrites. Annu Rev Neurosci 1996, 19: 165–186.

    Article  CAS  Google Scholar 

  47. Häusser M, Spruston N, Stuart G. Diversity and dynamics of dendritic signaling. Science 2000, 290: 739–744.

    Article  Google Scholar 

  48. Katz E, Stoler O, Scheller A, Khrapunsky Y, Goebbels S, Kirchhoff F, et al. Role of sodium channel subtype in action potential generation by neocortical pyramidal neurons. Proc Natl Acad Sci U S A 2018, 115: E7184–E7192.

    Article  CAS  Google Scholar 

  49. Lu JT, Tucciarone J, Padilla-Coreano N, He M, Gordon JA, Huang ZJ. Selective inhibitory control of pyramidal neuron ensembles and cortical subnetworks by chandelier cells. Nat Neurosci 2017, 20: 1377–1383.

    Article  CAS  Google Scholar 

  50. Wang XJ, Tucciarone J, Jiang SQ, Yin FF, Wang BS, Wang DK, et al. Genetic single neuron anatomy reveals fine granularity of cortical axo-axonic cells. Cell Rep 2019, 26: 3145-3159.e5.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank Drs. Songting Li and Douglas Z. Zhou (Shanghai Jiao Tong University) for their comments on the manuscript. This work was supported by the National Natural Science Foundation of China (32130043 and 32071025) and the Interdisciplinary Research Fund of Beijing Normal University, China.

Author information

Author notes

  1. Ziwei Shang and Junhao Huang contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Cognitive Neuroscience and Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, 100875, China

    Ziwei Shang, Junhao Huang, Nan Liu & Xiaohui Zhang

Authors
  1. Ziwei Shang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junhao Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaohui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaohui Zhang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 671 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shang, Z., Huang, J., Liu, N. et al. Bi-directional Control of Synaptic Input Summation and Spike Generation by GABAergic Inputs at the Axon Initial Segment. Neurosci. Bull. 39, 1–13 (2023). https://doi.org/10.1007/s12264-022-00887-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-022-00887-w

Keywords

Search

Navigation