Severe deficiency of the voltage-gated sodium channel Na V 1.2 elevates neuronal excitability in adult mice.

Autor:	Zhang J; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA., Chen X; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA., Eaton M; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA., Wu J; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA., Ma Z; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA., Lai S; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA., Park A; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA., Ahmad TS; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA., Que Z; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA., Lee JH; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA., Xiao T; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA., Li Y; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA., Wang Y; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA., Olivero-Acosta MI; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA., Schaber JA; Bioscience Imaging Facility, Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA., Jayant K; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA., Yuan C; Davidson School of Chemical Engineering, Purdue University, West Lafayette, IN 47907, USA., Huang Z; Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China., Lanman NA; Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA., Skarnes WC; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA., Yang Y; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA. Electronic address: yangyang@purdue.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2021 Aug 03; Vol. 36 (5), pp. 109495.
DOI:	10.1016/j.celrep.2021.109495
Abstrakt:	Scn2a encodes the voltage-gated sodium channel Na V 1.2, a main mediator of neuronal action potential firing. The current paradigm suggests that Na V 1.2 gain-of-function variants enhance neuronal excitability, resulting in epilepsy, whereas Na V 1.2 deficiency impairs neuronal excitability, contributing to autism. However, this paradigm does not explain why ∼20%-30% of individuals with Na V 1.2 deficiency still develop seizures. Here, we report the counterintuitive finding that severe Na V 1.2 deficiency results in increased neuronal excitability. Using a Na V 1.2-deficient mouse model, we show enhanced intrinsic excitability of principal neurons in the prefrontal cortex and striatum, brain regions known to be involved in Scn2a-related seizures. This increased excitability is autonomous and reversible by genetic restoration of Scn2a expression in adult mice. RNA sequencing reveals downregulation of multiple potassium channels, including K V 1.1. Correspondingly, K V channel openers alleviate the hyperexcitability of Na V 1.2-deficient neurons. This unexpected neuronal hyperexcitability may serve as a cellular basis underlying Na V 1.2 deficiency-related seizures. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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