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Non-synaptic Cell-Autonomous Mechanisms Underlie Neuronal Hyperactivity in a Genetic Model of PIK3CA -Driven Intractable Epilepsy.

التفاصيل البيبلوغرافية
العنوان: Non-synaptic Cell-Autonomous Mechanisms Underlie Neuronal Hyperactivity in a Genetic Model of PIK3CA -Driven Intractable Epilepsy.
المؤلفون: Roy A; Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bengaluru, India., Han VZ; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, United States.; Department of Biology, University of Washington, Seattle, WA, United States., Bard AM; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, United States., Wehle DT; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, United States.; Graduate Program in Neuroscience, University of Washington, Seattle, WA, United States., Smith SEP; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, United States.; Department of Pediatrics, University of Washington, Seattle, WA, United States., Ramirez JM; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, United States.; Department of Pediatrics, University of Washington, Seattle, WA, United States.; Department of Neurological Surgery, University of Washington, Seattle, WA, United States.; Department of Physiology and Biophysics, University of Washington, Seattle, WA, United States., Kalume F; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, United States.; Department of Neurological Surgery, University of Washington, Seattle, WA, United States.; Department of Pharmacology, University of Washington, Seattle, WA, United States., Millen KJ; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, United States.; Department of Pediatrics, University of Washington, Seattle, WA, United States.
المصدر: Frontiers in molecular neuroscience [Front Mol Neurosci] 2021 Nov 26; Vol. 14, pp. 772847. Date of Electronic Publication: 2021 Nov 26 (Print Publication: 2021).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Frontiers Research Foundation Country of Publication: Switzerland NLM ID: 101477914 Publication Model: eCollection Cited Medium: Print ISSN: 1662-5099 (Print) Linking ISSN: 16625099 NLM ISO Abbreviation: Front Mol Neurosci Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: Lausanne, Switzerland : Frontiers Research Foundation, 2008-
مستخلص: Patients harboring mutations in the PI3K-AKT-MTOR pathway-encoding genes often develop a spectrum of neurodevelopmental disorders including epilepsy. A significant proportion remains unresponsive to conventional anti-seizure medications. Understanding mutation-specific pathophysiology is thus critical for molecularly targeted therapies. We previously determined that mouse models expressing a patient-related activating mutation in PIK3CA , encoding the p110α catalytic subunit of phosphoinositide-3-kinase (PI3K), are epileptic and acutely treatable by PI3K inhibition, irrespective of dysmorphology. Here we report the physiological mechanisms underlying this dysregulated neuronal excitability. In vivo , we demonstrate epileptiform events in the Pik3ca mutant hippocampus. By ex vivo analyses, we show that Pik3ca-driven hyperactivation of hippocampal pyramidal neurons is mediated by changes in multiple non-synaptic, cell-intrinsic properties. Finally, we report that acute inhibition of PI3K or AKT, but not MTOR activity, suppresses the intrinsic hyperactivity of the mutant neurons. These acute mechanisms are distinct from those causing neuronal hyperactivity in other AKT-MTOR epileptic models and define parameters to facilitate the development of new molecularly rational therapeutic interventions for intractable epilepsy.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Roy, Han, Bard, Wehle, Smith, Ramirez, Kalume and Millen.)
References: Sci Transl Med. 2020 Nov 18;12(570):. (PMID: 33208499)
Sci Rep. 2015 Dec 11;5:17162. (PMID: 26657992)
Epilepsia. 2015 Dec;56(12):1879-89. (PMID: 26514993)
Mol Cancer Ther. 2012 Apr;11(4):873-87. (PMID: 22294718)
iScience. 2021 Jan 29;24(2):102118. (PMID: 33659881)
Brain Behav Immun. 2019 Jan;75:84-93. (PMID: 30243822)
Cell Biosci. 2020 Mar 10;10:31. (PMID: 32175074)
Cold Spring Harb Perspect Med. 2015 Jun 01;5(6):. (PMID: 26033084)
Epilepsia. 2009 Dec;50(12):2514-25. (PMID: 19674056)
Int J Mol Sci. 2019 Jan 29;20(3):. (PMID: 30699993)
Mol Cancer Ther. 2012 Feb;11(2):317-28. (PMID: 22188813)
Ann Clin Transl Neurol. 2021 Feb;8(2):485-490. (PMID: 33434304)
J Pediatr. 2014 May;164(5):1195-200. (PMID: 24518170)
Respir Physiol Neurobiol. 2013 Nov 1;189(2):324-8. (PMID: 23850567)
Mol Cancer. 2019 Feb 19;18(1):26. (PMID: 30782187)
Elife. 2015 Dec 03;4:. (PMID: 26633882)
Front Neurol Neurosci. 2014;34:121-42. (PMID: 24777136)
Exp Mol Med. 2011 May 31;43(5):231-74. (PMID: 21467839)
Elife. 2019 May 16;8:. (PMID: 31094678)
Ann Neurol. 2020 Dec;88(6):1077-1094. (PMID: 32856318)
J Neurosci. 2013 May 22;33(21):9056-67. (PMID: 23699517)
Neurobiol Dis. 2015 May;77:141-54. (PMID: 25766678)
Acta Neurol Scand. 2006 Feb;113(2):72-81. (PMID: 16411966)
Cold Spring Harb Perspect Med. 2019 Nov 1;9(11):. (PMID: 31427284)
Acta Neuropathol Commun. 2020 Apr 21;8(1):54. (PMID: 32317027)
Epilepsia. 2011 Jan;52(1):158-74. (PMID: 21219302)
Annu Rev Physiol. 2001;63:815-46. (PMID: 11181977)
Epilepsia. 2013 Jul;54(7):1251-61. (PMID: 23663038)
Epilepsia. 2000 Mar;41(3):297-307. (PMID: 10714401)
Brain. 2015 Jun;138(Pt 6):1613-28. (PMID: 25722288)
Expert Rev Neurother. 2013 Jun;13(6):627-38. (PMID: 23739000)
Neuroscience. 2017 Dec 26;367:200-210. (PMID: 29104031)
Nature. 2012 Aug 2;488(7409):43-8. (PMID: 22722829)
Nat Med. 2008 Aug;14(8):843-8. (PMID: 18568033)
Neuropharmacology. 2020 May 1;167:107750. (PMID: 31469995)
Am J Med Genet C Semin Med Genet. 2019 Dec;181(4):582-590. (PMID: 31441589)
J Korean Neurosurg Soc. 2019 May;62(3):272-287. (PMID: 31085953)
Orphanet J Rare Dis. 2021 Feb 27;16(1):109. (PMID: 33639990)
J Neurosci. 2019 Oct 23;39(43):8439-8456. (PMID: 31519824)
J Clin Neurophysiol. 2010 Dec;27(6):387-97. (PMID: 21076335)
Front Mol Neurosci. 2014 Mar 14;7:18. (PMID: 24672426)
Epilepsy Behav. 2008 Jul;13(1):25-31. (PMID: 18439878)
Ann Neurol. 2021 Aug;90(2):285-299. (PMID: 34180075)
J Neurol Sci. 2013 Sep 15;332(1-2):4-15. (PMID: 23773767)
Neurochem Res. 2017 Jul;42(7):1894-1903. (PMID: 28462454)
Nature. 2020 Feb;578(7793):166-171. (PMID: 31996845)
Elife. 2019 Aug 12;8:. (PMID: 31403401)
Front Neuroanat. 2021 Apr 09;15:664695. (PMID: 33897381)
Nat Rev Neurol. 2016 Jul;12(7):379-92. (PMID: 27340022)
Biochem Soc Trans. 2020 Feb 28;48(1):301-315. (PMID: 32010943)
Int J Mol Sci. 2018 Nov 23;19(12):. (PMID: 30477115)
Nature. 2018 Jun;558(7711):540-546. (PMID: 29899452)
Cell Biol Int. 1998 Nov;22(11-12):793-805. (PMID: 10873292)
Ann Neurol. 2007 Feb;61(2):139-52. (PMID: 17279540)
Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):467-72. (PMID: 11756682)
N Engl J Med. 2010 Nov 4;363(19):1801-11. (PMID: 21047224)
J Neurophysiol. 2019 Nov 1;122(5):1861-1873. (PMID: 31461373)
Neuropharmacology. 2020 Apr;166:107811. (PMID: 31790717)
معلومات مُعتمدة: R01 NS099027 United States NS NINDS NIH HHS; R01 NS102796 United States NS NINDS NIH HHS
فهرسة مساهمة: Keywords: AZD5363 (PubChem CID: 25227436); BKM120 (buparlisib); PI3K; RAD001 (everolimus); electrophysiology; epilepsy; hippocampus; mouse model
تواريخ الأحداث: Date Created: 20211213 Latest Revision: 20221210
رمز التحديث: 20240829
مُعرف محوري في PubMed: PMC8662737
DOI: 10.3389/fnmol.2021.772847
PMID: 34899181
قاعدة البيانات: MEDLINE
الوصف
تدمد:1662-5099
DOI:10.3389/fnmol.2021.772847