*Result*: Adaptations of the axon initial segment in fast-spiking interneurons of the human neocortex support low action potential thresholds.
Title:
Adaptations of the axon initial segment in fast-spiking interneurons of the human neocortex support low action potential thresholds.
Authors:
Bakos E; Hungarian Center of Excellence for Molecular Medicine Research Group for Human Neuron Physiology and Therapy, Szeged, Hungary.; Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary., Tiszlavicz Á; Hungarian Center of Excellence for Molecular Medicine Research Group for Human Neuron Physiology and Therapy, Szeged, Hungary., Szegedi V; Hungarian Center of Excellence for Molecular Medicine Research Group for Human Neuron Physiology and Therapy, Szeged, Hungary.; Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary., Douida A; Hungarian Center of Excellence for Molecular Medicine Research Group for Human Neuron Physiology and Therapy, Szeged, Hungary., Furdan S; Hungarian Center of Excellence for Molecular Medicine Research Group for Human Neuron Physiology and Therapy, Szeged, Hungary., Welter DK; European Molecular Biology Laboratory, Heidelberg, Germany., Landry JM; European Molecular Biology Laboratory, Heidelberg, Germany., Bende B; Hungarian Centre of Excellence for Molecular Medicine Research Group for Translational Medicine Development, Szeged, Hungary., Hutoczki G; Department of Neurosurgery, University of Debrecen Clinical Centre, Debrecen Hungary., Barzo P; Department of Neurosurgery, University of Szeged, Szeged, Hungary., Tamas G; ELKH-SZTE Research Group for Cortical Microcircuits, Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary., Benes V; European Molecular Biology Laboratory, Heidelberg, Germany., Szucs A; Neuronal Cell Biology Research Group, Eötvös Loránd University, Budapest, Hungary., Lamsa K; Hungarian Center of Excellence for Molecular Medicine Research Group for Human Neuron Physiology and Therapy, Szeged, Hungary.; Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary.
Source:
PLoS biology [PLoS Biol] 2025 Dec 10; Vol. 23 (12), pp. e3003549. Date of Electronic Publication: 2025 Dec 10 (Print Publication: 2025).
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Public Library of Science Country of Publication: United States NLM ID: 101183755 Publication Model: eCollection Cited Medium: Internet ISSN: 1545-7885 (Electronic) Linking ISSN: 15449173 NLM ISO Abbreviation: PLoS Biol Subsets: MEDLINE
Imprint Name(s):
Original Publication: San Francisco, CA : Public Library of Science, [2003]-
MeSH Terms:
Neocortex*/physiology , Neocortex*/cytology , Neocortex*/metabolism , Action Potentials*/physiology , Interneurons*/physiology , Interneurons*/metabolism , Interneurons*/cytology , Axon Initial Segment*/physiology , Axon Initial Segment*/metabolism , Axons*/physiology, Parvalbumins/metabolism ; Kv1.1 Potassium Channel/metabolism ; Kv1.2 Potassium Channel/metabolism ; Humans ; Animals ; Mice ; Male ; Female ; Adult ; Middle Aged
Comments:
Update of: bioRxiv. 2025 Jul 23:2024.10.28.620622. doi: 10.1101/2024.10.28.620622.. (PMID: 40777488)
References:
Cereb Cortex. 2021 Jan 5;31(2):845-872. (PMID: 33068000)
J Neurophysiol. 2008 Oct;100(4):2348-60. (PMID: 18632882)
eNeuro. 2017 Oct 13;4(5):. (PMID: 29034319)
Front Neuroanat. 2008 Mar 28;1:3. (PMID: 18958197)
Cell Rep. 2018 Apr 24;23(4):951-958. (PMID: 29694902)
Elife. 2020 Mar 30;9:. (PMID: 32223890)
J Anat. 2015 Oct;227(4):384-93. (PMID: 24839870)
Neuron. 2012 Jan 26;73(2):235-47. (PMID: 22284179)
Nat Protoc. 2014 Jan;9(1):171-81. (PMID: 24385147)
Science. 2014 Aug 1;345(6196):1255263. (PMID: 25082707)
Cell Mol Neurobiol. 2023 Dec 20;44(1):8. (PMID: 38123823)
Nature. 2019 Sep;573(7772):61-68. (PMID: 31435019)
Int J Mol Sci. 2020 Apr 22;21(8):. (PMID: 32331416)
Front Neuroinform. 2021 Feb 18;15:580873. (PMID: 33679362)
Nat Neurosci. 2018 Sep;21(9):1185-1195. (PMID: 30150662)
Cell. 2023 Dec 21;186(26):5766-5783.e25. (PMID: 38134874)
Front Psychiatry. 2021 Jun 18;12:679960. (PMID: 34220586)
Trends Neurosci. 2024 Jul;47(7):491-505. (PMID: 38897852)
Neuron. 2008 May 8;58(3):387-400. (PMID: 18466749)
Acta Neuropathol Commun. 2023 Mar 7;11(1):34. (PMID: 36882863)
Bioinformatics. 2013 Jul 15;29(14):1840-1. (PMID: 23681123)
Front Neuroanat. 2017 Nov 07;11:100. (PMID: 29163073)
Nature. 2016 May 04;533(7603):390-2. (PMID: 27144364)
PLoS Genet. 2008 Nov;4(11):e1000271. (PMID: 19023414)
Nature. 2021 Oct;598(7879):151-158. (PMID: 34616067)
Nat Commun. 2021 May 3;12(1):2497. (PMID: 33941783)
Trends Neurosci. 2008 Dec;31(12):637-44. (PMID: 18848363)
Eur Neuropsychopharmacol. 2024 May;82:44-52. (PMID: 38490084)
Curr Opin Neurobiol. 2005 Aug;15(4):444-53. (PMID: 16026978)
Mol Neuropsychiatry. 2019 Feb;4(4):204-215. (PMID: 30815456)
Methods Mol Biol. 2024;2752:227-243. (PMID: 38194038)
Mol Psychiatry. 2023 Dec;28(12):4954-4967. (PMID: 37419975)
Science. 2023 Oct 13;382(6667):eade9516. (PMID: 37824638)
Sci Adv. 2023 Oct 13;9(41):eadf0708. (PMID: 37824618)
Cereb Cortex. 2022 May 31;32(11):2343-2357. (PMID: 34550325)
Brain Behav Evol. 2015;86(3-4):145-63. (PMID: 26418466)
Prog Neurobiol. 2011 Jul;94(2):115-32. (PMID: 21530607)
J Neurosci. 2012 Jun 27;32(26):8940-51. (PMID: 22745494)
J Neurosci. 2008 May 28;28(22):5731-9. (PMID: 18509034)
J Neurosci. 2008 Dec 31;28(53):14329-40. (PMID: 19118165)
Ann N Y Acad Sci. 2009 Mar;1156:44-67. (PMID: 19338502)
G3 (Bethesda). 2018 Jan 4;8(1):79-89. (PMID: 29118030)
J Neurosci. 1997 Jul 15;17(14):5509-27. (PMID: 9204933)
Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18571-6. (PMID: 23090991)
Neurologia (Engl Ed). 2018 May;33(4):254-265. (PMID: 26304653)
Cereb Cortex. 1997 Sep;7(6):476-86. (PMID: 9276173)
Science. 2022 Mar 11;375(6585):eabj5861. (PMID: 35271334)
Neuron. 2018 Oct 24;100(2):294-313. (PMID: 30359598)
J Cell Biol. 2007 Feb 12;176(4):509-19. (PMID: 17283186)
J Cereb Blood Flow Metab. 2012 Jul;32(7):1222-32. (PMID: 22434069)
J Neurosci. 2013 Oct 23;33(43):17197-208. (PMID: 24155324)
Neuropsychopharmacology. 2021 Jan;46(2):279-287. (PMID: 32722660)
Elife. 2020 Jun 04;9:. (PMID: 32496194)
PLoS Biol. 2014 Sep 09;12(9):e1001944. (PMID: 25203314)
Nature. 2023 Aug;620(7972):145-153. (PMID: 37468639)
J Neurosci. 1998 Oct 15;18(20):8111-25. (PMID: 9763458)
Front Genet. 2013 Oct 28;4:213. (PMID: 24194747)
Science. 2023 Oct 13;382(6667):eadf6484. (PMID: 37824669)
Neural Plast. 2016;2016:6808293. (PMID: 27493806)
Development. 2024 Feb 15;151(4):. (PMID: 38369736)
Front Cell Neurosci. 2017 Nov 06;11:332. (PMID: 29170630)
Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886)
J Biotechnol. 2024 Jun 20;389:1-12. (PMID: 38697361)
Cell Rep. 2024 Apr 23;43(4):114100. (PMID: 38607921)
Trends Cogn Sci. 2022 Nov;26(11):909-922. (PMID: 36117080)
Nat Ecol Evol. 2023 Nov;7(11):1930-1943. (PMID: 37667001)
Front Neural Circuits. 2007 Nov 02;1:4. (PMID: 18946546)
Elife. 2022 Nov 07;11:. (PMID: 36342372)
Proc Natl Acad Sci U S A. 2016 Dec 20;113(51):14841-14846. (PMID: 27930291)
Nature. 2001 Jan 4;409(6816):88-92. (PMID: 11343119)
Ann N Y Acad Sci. 2018 May;1420(1):46-61. (PMID: 29749636)
Mol Brain. 2019 Jul 4;12(1):64. (PMID: 31272478)
Front Cell Neurosci. 2016 Oct 18;10:239. (PMID: 27803650)
J Cereb Blood Flow Metab. 2014 Aug;34(8):1270-82. (PMID: 24896567)
J Neurosci. 1999 Nov 1;19(21):9332-45. (PMID: 10531438)
Cell. 2012 Apr 13;149(2):483-96. (PMID: 22500809)
Front Cell Neurosci. 2016 Oct 25;10:250. (PMID: 27826229)
Cell Rep. 2022 Dec 13;41(11):111787. (PMID: 36516769)
J Neurosci. 2018 Feb 28;38(9):2135-2145. (PMID: 29378864)
Trends Neurosci. 2012 Jan;35(1):57-67. (PMID: 22154068)
Neuron. 2018 Dec 5;100(5):1194-1208.e5. (PMID: 30392798)
J Physiol. 2011 Nov 1;589(Pt 21):5125-42. (PMID: 21911608)
Neuron. 2007 Aug 16;55(4):633-47. (PMID: 17698015)
Elife. 2020 Jan 09;9:. (PMID: 31916939)
PLoS Biol. 2023 Feb 6;21(2):e3002001. (PMID: 36745683)
J Physiol. 2009 Jan 15;587(1):87-100. (PMID: 19001045)
Neuron. 2016 Jul 20;91(2):260-92. (PMID: 27477017)
Nat Rev Genet. 2024 Jan;25(1):26-45. (PMID: 37507490)
J Neurophysiol. 2008 Oct;100(4):2348-60. (PMID: 18632882)
eNeuro. 2017 Oct 13;4(5):. (PMID: 29034319)
Front Neuroanat. 2008 Mar 28;1:3. (PMID: 18958197)
Cell Rep. 2018 Apr 24;23(4):951-958. (PMID: 29694902)
Elife. 2020 Mar 30;9:. (PMID: 32223890)
J Anat. 2015 Oct;227(4):384-93. (PMID: 24839870)
Neuron. 2012 Jan 26;73(2):235-47. (PMID: 22284179)
Nat Protoc. 2014 Jan;9(1):171-81. (PMID: 24385147)
Science. 2014 Aug 1;345(6196):1255263. (PMID: 25082707)
Cell Mol Neurobiol. 2023 Dec 20;44(1):8. (PMID: 38123823)
Nature. 2019 Sep;573(7772):61-68. (PMID: 31435019)
Int J Mol Sci. 2020 Apr 22;21(8):. (PMID: 32331416)
Front Neuroinform. 2021 Feb 18;15:580873. (PMID: 33679362)
Nat Neurosci. 2018 Sep;21(9):1185-1195. (PMID: 30150662)
Cell. 2023 Dec 21;186(26):5766-5783.e25. (PMID: 38134874)
Front Psychiatry. 2021 Jun 18;12:679960. (PMID: 34220586)
Trends Neurosci. 2024 Jul;47(7):491-505. (PMID: 38897852)
Neuron. 2008 May 8;58(3):387-400. (PMID: 18466749)
Acta Neuropathol Commun. 2023 Mar 7;11(1):34. (PMID: 36882863)
Bioinformatics. 2013 Jul 15;29(14):1840-1. (PMID: 23681123)
Front Neuroanat. 2017 Nov 07;11:100. (PMID: 29163073)
Nature. 2016 May 04;533(7603):390-2. (PMID: 27144364)
PLoS Genet. 2008 Nov;4(11):e1000271. (PMID: 19023414)
Nature. 2021 Oct;598(7879):151-158. (PMID: 34616067)
Nat Commun. 2021 May 3;12(1):2497. (PMID: 33941783)
Trends Neurosci. 2008 Dec;31(12):637-44. (PMID: 18848363)
Eur Neuropsychopharmacol. 2024 May;82:44-52. (PMID: 38490084)
Curr Opin Neurobiol. 2005 Aug;15(4):444-53. (PMID: 16026978)
Mol Neuropsychiatry. 2019 Feb;4(4):204-215. (PMID: 30815456)
Methods Mol Biol. 2024;2752:227-243. (PMID: 38194038)
Mol Psychiatry. 2023 Dec;28(12):4954-4967. (PMID: 37419975)
Science. 2023 Oct 13;382(6667):eade9516. (PMID: 37824638)
Sci Adv. 2023 Oct 13;9(41):eadf0708. (PMID: 37824618)
Cereb Cortex. 2022 May 31;32(11):2343-2357. (PMID: 34550325)
Brain Behav Evol. 2015;86(3-4):145-63. (PMID: 26418466)
Prog Neurobiol. 2011 Jul;94(2):115-32. (PMID: 21530607)
J Neurosci. 2012 Jun 27;32(26):8940-51. (PMID: 22745494)
J Neurosci. 2008 May 28;28(22):5731-9. (PMID: 18509034)
J Neurosci. 2008 Dec 31;28(53):14329-40. (PMID: 19118165)
Ann N Y Acad Sci. 2009 Mar;1156:44-67. (PMID: 19338502)
G3 (Bethesda). 2018 Jan 4;8(1):79-89. (PMID: 29118030)
J Neurosci. 1997 Jul 15;17(14):5509-27. (PMID: 9204933)
Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18571-6. (PMID: 23090991)
Neurologia (Engl Ed). 2018 May;33(4):254-265. (PMID: 26304653)
Cereb Cortex. 1997 Sep;7(6):476-86. (PMID: 9276173)
Science. 2022 Mar 11;375(6585):eabj5861. (PMID: 35271334)
Neuron. 2018 Oct 24;100(2):294-313. (PMID: 30359598)
J Cell Biol. 2007 Feb 12;176(4):509-19. (PMID: 17283186)
J Cereb Blood Flow Metab. 2012 Jul;32(7):1222-32. (PMID: 22434069)
J Neurosci. 2013 Oct 23;33(43):17197-208. (PMID: 24155324)
Neuropsychopharmacology. 2021 Jan;46(2):279-287. (PMID: 32722660)
Elife. 2020 Jun 04;9:. (PMID: 32496194)
PLoS Biol. 2014 Sep 09;12(9):e1001944. (PMID: 25203314)
Nature. 2023 Aug;620(7972):145-153. (PMID: 37468639)
J Neurosci. 1998 Oct 15;18(20):8111-25. (PMID: 9763458)
Front Genet. 2013 Oct 28;4:213. (PMID: 24194747)
Science. 2023 Oct 13;382(6667):eadf6484. (PMID: 37824669)
Neural Plast. 2016;2016:6808293. (PMID: 27493806)
Development. 2024 Feb 15;151(4):. (PMID: 38369736)
Front Cell Neurosci. 2017 Nov 06;11:332. (PMID: 29170630)
Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886)
J Biotechnol. 2024 Jun 20;389:1-12. (PMID: 38697361)
Cell Rep. 2024 Apr 23;43(4):114100. (PMID: 38607921)
Trends Cogn Sci. 2022 Nov;26(11):909-922. (PMID: 36117080)
Nat Ecol Evol. 2023 Nov;7(11):1930-1943. (PMID: 37667001)
Front Neural Circuits. 2007 Nov 02;1:4. (PMID: 18946546)
Elife. 2022 Nov 07;11:. (PMID: 36342372)
Proc Natl Acad Sci U S A. 2016 Dec 20;113(51):14841-14846. (PMID: 27930291)
Nature. 2001 Jan 4;409(6816):88-92. (PMID: 11343119)
Ann N Y Acad Sci. 2018 May;1420(1):46-61. (PMID: 29749636)
Mol Brain. 2019 Jul 4;12(1):64. (PMID: 31272478)
Front Cell Neurosci. 2016 Oct 18;10:239. (PMID: 27803650)
J Cereb Blood Flow Metab. 2014 Aug;34(8):1270-82. (PMID: 24896567)
J Neurosci. 1999 Nov 1;19(21):9332-45. (PMID: 10531438)
Cell. 2012 Apr 13;149(2):483-96. (PMID: 22500809)
Front Cell Neurosci. 2016 Oct 25;10:250. (PMID: 27826229)
Cell Rep. 2022 Dec 13;41(11):111787. (PMID: 36516769)
J Neurosci. 2018 Feb 28;38(9):2135-2145. (PMID: 29378864)
Trends Neurosci. 2012 Jan;35(1):57-67. (PMID: 22154068)
Neuron. 2018 Dec 5;100(5):1194-1208.e5. (PMID: 30392798)
J Physiol. 2011 Nov 1;589(Pt 21):5125-42. (PMID: 21911608)
Neuron. 2007 Aug 16;55(4):633-47. (PMID: 17698015)
Elife. 2020 Jan 09;9:. (PMID: 31916939)
PLoS Biol. 2023 Feb 6;21(2):e3002001. (PMID: 36745683)
J Physiol. 2009 Jan 15;587(1):87-100. (PMID: 19001045)
Neuron. 2016 Jul 20;91(2):260-92. (PMID: 27477017)
Nat Rev Genet. 2024 Jan;25(1):26-45. (PMID: 37507490)
Grant Information:
U01 MH114812 United States MH NIMH NIH HHS; UM1 MH130981 United States MH NIMH NIH HHS
Substance Nomenclature:
0 (Parvalbumins)
147173-20-4 (Kv1.1 Potassium Channel)
0 (Kv1.2 Potassium Channel)
147173-20-4 (Kv1.1 Potassium Channel)
0 (Kv1.2 Potassium Channel)
Entry Date(s):
Date Created: 20251210 Date Completed: 20251217 Latest Revision: 20260116
Update Code:
20260130
PubMed Central ID:
PMC12798858
DOI:
10.1371/journal.pbio.3003549
PMID:
41370321
Database:
MEDLINE
*Further Information*
*The mammalian brain exhibits notable interspecies variation. Microanatomical and molecular differences in homologous neurons, those with similar locations and developmental origins across species, are best characterized in the neocortical mantle, the center of complex brain functions; however, the purpose of these differences remains unclear. We performed whole-cell microelectrode recordings along with microanatomical and molecular analyses of human fast-spiking parvalbumin (pvalb)-expressing interneurons in neocortical tissue resected during brain surgery, comparing them with similar data obtained from the mouse neocortex. The action potential (AP) firing threshold was lower in human neurons than in mouse neurons. This was due to a deficiency in low-voltage-activated inhibitory Kv1.1 and Kv1.2 potassium channels in the axon initial segment (AIS), a specialized axonal region that determines AP threshold and initiation, in human cells. In contrast, Kv1 ion channels were prominent in mouse neurons. The AIS was also moderately elongated in humans. Computational simulations of fast-spiking interneurons revealed that the human-type AIS lowers the AP threshold and shortens the time lag for AP initiation. We found that the low membrane AP firing threshold in pvalb neurons is closely linked to slow membrane potential kinetics in the soma. Thus, the human AIS supports fast in-fast out circuit function in human pvalb neurons, compensating for electrically slow somatic membrane responses. When formulating therapeutic strategies that involve fast-spiking neurons, it is crucial to take into account the molecular and functional species differences.
(Copyright: © 2025 Bakos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)*
*The authors have declared that no competing interests exist.*