• Tsc1 deletion in Purkinje neur...

*Result*: Tsc1 deletion in Purkinje neurons disrupts the axon initial segment, impairing excitability and cerebellar function.

Title:
Tsc1 deletion in Purkinje neurons disrupts the axon initial segment, impairing excitability and cerebellar function.
Authors:
Brown SP; Department of Biology, Miami University, Oxford, OH 45056, United States., Jena AK; Department of Biology, Miami University, Oxford, OH 45056, United States., Osko JJ; Department of Biology, Miami University, Oxford, OH 45056, United States., Ransdell JL; Department of Biology, Miami University, Oxford, OH 45056, United States. Electronic address: ransdejl@miamioh.edu.
Source:
Neurobiology of disease [Neurobiol Dis] 2025 Apr; Vol. 207, pp. 106856. Date of Electronic Publication: 2025 Feb 25.
Publication Type:
Journal Article; Research Support, N.I.H., Extramural
Language:
English
Journal Info:
Publisher: Academic Press Country of Publication: United States NLM ID: 9500169 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-953X (Electronic) Linking ISSN: 09699961 NLM ISO Abbreviation: Neurobiol Dis Subsets: MEDLINE
Imprint Name(s):
Publication: San Diego, CA : Academic Press
Original Publication: Oxford : Blackwell Science, c1994-
MeSH Terms:
Purkinje Cells*/physiology , Purkinje Cells*/metabolism , Purkinje Cells*/pathology , Tuberous Sclerosis Complex 1 Protein*/genetics , Axon Initial Segment*/physiology , Axon Initial Segment*/metabolism , Cerebellum*/physiology , Cerebellum*/metabolism , Cerebellum*/physiopathology, Action Potentials/physiology ; Animals ; Mice ; Mice, Inbred C57BL ; Male
Comments:
Update of: bioRxiv. 2025 Feb 01:2025.01.31.635932. doi: 10.1101/2025.01.31.635932.. (PMID: 39974887)
References:
Nat Neurosci. 2010 Jan;13(1):133-40. (PMID: 20023653)
Rev Neurol. 2013 Dec 16;57(12):556-68. (PMID: 24288105)
Sci Rep. 2018 Jan 18;8(1):1022. (PMID: 29348594)
Front Cell Neurosci. 2014 Dec 08;8:414. (PMID: 25538564)
J Neurosci. 2016 Apr 20;36(16):4421-33. (PMID: 27098687)
J Neurophysiol. 2007 May;97(5):3460-72. (PMID: 17314237)
Neurobiol Dis. 2016 May;89:36-45. (PMID: 26807988)
Exp Brain Res. 1967;4(1):43-57. (PMID: 4386325)
Neurobiol Dis. 2009 Jan;33(1):81-8. (PMID: 18930825)
Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6861-5. (PMID: 1495975)
J Child Neurol. 2004 Sep;19(9):675-9. (PMID: 15563013)
Sci Rep. 2017 Feb 09;7:42006. (PMID: 28181483)
Mol Cell Neurosci. 2013 Sep;56:393-403. (PMID: 23891806)
J Neurophysiol. 2009 Oct;102(4):2161-75. (PMID: 19571202)
J Dermatol. 1992 Nov;19(11):914-9. (PMID: 1293183)
Brain. 1998 May;121 ( Pt 5):889-905. (PMID: 9619192)
Exp Brain Res. 1970 Nov 26;11(4):327-42. (PMID: 5496934)
Front Syst Neurosci. 2014 May 20;8:92. (PMID: 24904314)
Trends Immunol. 2004 Jun;25(6):280-8. (PMID: 15145317)
Front Cell Neurosci. 2015 Jan 13;8:451. (PMID: 25628536)
J Comp Neurol. 1992 Dec 22;326(4):549-60. (PMID: 1484123)
Front Behav Neurosci. 2024 Dec 17;18:1474066. (PMID: 39741564)
J Cell Biol. 2007 Jun 4;177(5):857-70. (PMID: 17548513)
J Neurosci. 2012 May 23;32(21):7232-43. (PMID: 22623668)
Autophagy. 2011 Oct;7(10):1173-86. (PMID: 21808151)
Biochem Biophys Res Commun. 2005 Jun 17;331(4):1216-21. (PMID: 15883005)
Cell Rep. 2018 Oct 9;25(2):357-367.e4. (PMID: 30304677)
Neuropsychopharmacology. 2016 May;41(6):1457-66. (PMID: 26538449)
Nat Neurosci. 2014 Dec;17(12):1664-72. (PMID: 25362473)
J Child Neurol. 2008 May;23(5):520-5. (PMID: 18160549)
J Neurosci. 2007 Oct 10;27(41):11065-74. (PMID: 17928448)
Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13571-6. (PMID: 12271141)
Neuromolecular Med. 2006;8(4):531-46. (PMID: 17028374)
Curr Biol. 2003 Aug 5;13(15):1259-68. (PMID: 12906785)
Genesis. 2000 Nov-Dec;28(3-4):93-8. (PMID: 11105049)
J Neurosci. 2011 Sep 7;31(36):13002-14. (PMID: 21900579)
Cell Rep. 2017 Apr 18;19(3):532-544. (PMID: 28423317)
Cancer Res. 2007 Jul 1;67(13):6263-9. (PMID: 17616684)
Immunol Rev. 2012 Mar;246(1):239-53. (PMID: 22435559)
Genet Med. 2007 Feb;9(2):88-100. (PMID: 17304050)
J Neurodev Disord. 2023 Sep 14;15(1):32. (PMID: 37710171)
Neuron. 1994 Sep;13(3):703-12. (PMID: 7917300)
Cell Rep. 2023 Dec 26;42(12):113533. (PMID: 38048226)
Mol Cancer Res. 2015 Dec;13(12):1602-14. (PMID: 26374334)
J Neurophysiol. 2006 Aug;96(2):785-93. (PMID: 16687615)
Hum Mol Genet. 2009 Apr 15;18(R1):R94-100. (PMID: 19297407)
Brain Res. 1972 Oct 13;45(1):15-29. (PMID: 4116421)
J Neurosci. 2006 Feb 15;26(7):1935-44. (PMID: 16481425)
Genes Dev. 2002 Jun 15;16(12):1472-87. (PMID: 12080086)
J Neurosci. 2015 Apr 29;35(17):6752-69. (PMID: 25926453)
J Cell Biol. 2007 Feb 12;176(4):509-19. (PMID: 17283186)
J Biol Chem. 2014 Sep 5;289(36):25227-40. (PMID: 24990947)
Neuron. 2013 May 8;78(3):510-22. (PMID: 23664616)
J Cell Biol. 2001 Nov 26;155(5):739-46. (PMID: 11724816)
Neuron. 2016 Jul 20;91(2):312-9. (PMID: 27346533)
J Neurosci. 2015 Aug 12;35(32):11292-307. (PMID: 26269637)
Genesis. 2004 Sep;40(1):45-51. (PMID: 15354293)
Neuron. 2014 Aug 6;83(3):518-32. (PMID: 25102558)
Cancer Biol Ther. 2003 Sep-Oct;2(5):471-6. (PMID: 14614311)
Epilepsia. 2007 Apr;48(4):617-30. (PMID: 17386056)
Cell Rep. 2018 Jun 12;23(11):3197-3208. (PMID: 29898392)
Hum Mol Genet. 2002 Mar 1;11(5):525-34. (PMID: 11875047)
Nat Rev Neurosci. 2007 Jun;8(6):451-65. (PMID: 17514198)
Exp Mol Med. 2022 Jul;54(7):867-877. (PMID: 35794211)
J Cell Biol. 1998 Nov 30;143(5):1295-304. (PMID: 9832557)
Experientia. 1964 Oct 15;20(10):575-6. (PMID: 5859224)
Nat Commun. 2016 Sep 01;7:12627. (PMID: 27581745)
J Cell Biol. 2008 Nov 17;183(4):635-40. (PMID: 19001126)
Cell. 1993 Dec 31;75(7):1305-15. (PMID: 8269512)
Nature. 2012 Aug 30;488(7413):647-51. (PMID: 22763451)
Nat Neurosci. 2017 Dec;20(12):1744-1751. (PMID: 29184200)
N Engl J Med. 2006 Sep 28;355(13):1345-56. (PMID: 17005952)
J Neurosci. 2010 Jun 2;30(22):7740-8. (PMID: 20519549)
Cell. 2006 Feb 10;124(3):471-84. (PMID: 16469695)
Grant Information:
R15 NS125560 United States NS NINDS NIH HHS
Contributed Indexing:
Keywords: Purkinje neuron; Sodium channel; Tuberous sclerosis; ankyrinG; tsc1
Substance Nomenclature:
0 (Tuberous Sclerosis Complex 1 Protein)
0 (Tsc1 protein, mouse)
Entry Date(s):
Date Created: 20250227 Date Completed: 20250510 Latest Revision: 20250827
Update Code:
20260130
PubMed Central ID:
PMC11997981
DOI:
10.1016/j.nbd.2025.106856
PMID:
40015654
Database:
MEDLINE

*Further Information*

*Loss-of-function mutations in tuberous sclerosis 1 (TSC1) are prevalent monogenic causes of autism spectrum disorder (ASD). Selective deletion of Tsc1 from mouse cerebellar Purkinje neurons has been shown to cause several ASD-linked behavioral impairments, which are linked to reduced Purkinje neuron repetitive firing rates. We used electrophysiology methods to investigate why Purkinje neuron-specific Tsc1 deletion (Tsc1<sup>mut/mut</sup>) impairs Purkinje neuron firing. These studies revealed a depolarized shift in action potential threshold voltage, an effect that we link to reduced expression of the fast-transient voltage-gated sodium (Nav) current in Tsc1<sup>mut/mut</sup> Purkinje neurons. The reduced Nav currents in these cells was associated with diminished secondary immunofluorescence from anti-pan Nav channel labeling at Purkinje neuron axon initial segments (AIS). Anti-ankyrinG immunofluorescence was also found to be significantly reduced at the AIS of Tsc1<sup>mut/mut</sup> Purkinje neurons, suggesting Tsc1 is necessary for the organization and functioning of the Purkinje neuron AIS. An analysis of the 1st and 2nd derivative of the action potential voltage-waveform supported this hypothesis, revealing spike initiation and propagation from the AIS of Tsc1<sup>mut/mut</sup> Purkinje neurons is impaired compared to age-matched control Purkinje neurons. Heterozygous Tsc1 deletion resulted in no significant changes in the firing properties of adult Purkinje neurons, and slight reductions in anti-pan Nav and anti-ankyrinG labeling at the Purkinje neuron AIS, revealing deficits in Purkinje neuron firing due to Tsc1 haploinsufficiency are delayed compared to age-matched Tsc1<sup>mut/mut</sup> Purkinje neurons. Together, these data reveal that the loss of Tsc1 impairs Purkinje neuron firing and membrane excitability through the dysregulation of proteins essential for AIS organization and function.
(Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)*

*Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.*