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Severe deficiency of voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice

View ORCID ProfileJingliang Zhang, Xiaoling Chen, Muriel Eaton, Shirong Lai, Anthony Park, Talha S. Ahmad, Jiaxiang Wu, Zhixiong Ma, Zhefu Que, Ji Hea Lee, Tiange Xiao, Yuansong Li, Yujia Wang, Maria I. Olivero-Acosta, James A. Schaber, Krishna Jayant, Zhuo Huang, Nadia A. Lanman, William C. Skarnes, View ORCID ProfileYang Yang
doi: https://doi.org/10.1101/2021.02.02.429384
Jingliang Zhang
1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University
2Purdue Institute for Integrative Neuroscience, Purdue University
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  • ORCID record for Jingliang Zhang
Xiaoling Chen
1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University
2Purdue Institute for Integrative Neuroscience, Purdue University
3Weldon School of Biomedical Engineering, Purdue University
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Muriel Eaton
1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University
2Purdue Institute for Integrative Neuroscience, Purdue University
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Shirong Lai
1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University
2Purdue Institute for Integrative Neuroscience, Purdue University
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Anthony Park
1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University
2Purdue Institute for Integrative Neuroscience, Purdue University
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Talha S. Ahmad
1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University
2Purdue Institute for Integrative Neuroscience, Purdue University
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Jiaxiang Wu
1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University
2Purdue Institute for Integrative Neuroscience, Purdue University
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Zhixiong Ma
1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University
2Purdue Institute for Integrative Neuroscience, Purdue University
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Zhefu Que
1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University
2Purdue Institute for Integrative Neuroscience, Purdue University
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Ji Hea Lee
1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University
2Purdue Institute for Integrative Neuroscience, Purdue University
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Tiange Xiao
1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University
2Purdue Institute for Integrative Neuroscience, Purdue University
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Yuansong Li
1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University
2Purdue Institute for Integrative Neuroscience, Purdue University
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Yujia Wang
1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University
2Purdue Institute for Integrative Neuroscience, Purdue University
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Maria I. Olivero-Acosta
1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University
2Purdue Institute for Integrative Neuroscience, Purdue University
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James A. Schaber
4Bioscience Imaging Facility, Bindley Bioscience Center, Purdue University
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Krishna Jayant
2Purdue Institute for Integrative Neuroscience, Purdue University
3Weldon School of Biomedical Engineering, Purdue University
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Zhuo Huang
5Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center
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Nadia A. Lanman
6Department of Comparative Pathobiology, Purdue University
7Purdue University Center for Cancer Research, Purdue University
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William C. Skarnes
8The Jackson Laboratory for Genomic Medicine
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Yang Yang
1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University
2Purdue Institute for Integrative Neuroscience, Purdue University
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  • ORCID record for Yang Yang
  • For correspondence: yangyang@purdue.edu
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Abstract

Scn2a encodes voltage-gated sodium channel NaV1.2, which mediates neuronal firing. The current paradigm suggests that NaV1.2 gain-of-function variants enhance neuronal excitability resulting in epilepsy, whereas NaV1.2 deficiency impairs neuronal excitability contributing to autism. In this paradigm, however, why about a third of patients with NaV1.2 deficiency still develop seizures remains a mystery. Here we challenge the conventional wisdom, reporting that neuronal excitability is increased with severe NaV1.2 deficiency. Using a unique gene-trap knockout mouse model of Scn2a, we found enhanced intrinsic excitabilities of principal neurons in the cortico-striatal circuit, known to be involved in Scn2a-related seizures. This increased excitability is autonomous, and is reversible by genetic restoration of Scn2a expression in adult mice. Mechanistic investigation reveals a compensatory downregulation of potassium channels including KV1.1, which could be targeted to alleviate neuronal hyperexcitability. Our unexpected findings may explain NaV1.2 deficiency-related epileptic seizures in humans and provide molecular targets for potential interventions.

TEASER Severe NaV1.2 deficiency results in neuronal hyperexcitability via the compensatory downregulation of potassium channels.

HIGHLIGHTS

  1. Severe NaV1.2 deficiency results in enhanced excitability of medium spiny neurons (MSNs) and pyramidal neurons in adult mice;

  2. Increased neuronal excitability in MSNs is accompanied by elevated voltage threshold;

  3. NaV1.2 deficiency-related hyperexcitability is reversible with the restoration of Scn2a expression, and is autonomous;

  4. The expression of the KV1.1 channel has a compensatory reduction in neurons with NaV1.2 deficiency, and KV channels openers normalize the neuronal excitability;

  5. The enhanced excitability in brain slices translates to elevated in vivo firing commonly associated with seizures.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 02, 2021.
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Severe deficiency of voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice
Jingliang Zhang, Xiaoling Chen, Muriel Eaton, Shirong Lai, Anthony Park, Talha S. Ahmad, Jiaxiang Wu, Zhixiong Ma, Zhefu Que, Ji Hea Lee, Tiange Xiao, Yuansong Li, Yujia Wang, Maria I. Olivero-Acosta, James A. Schaber, Krishna Jayant, Zhuo Huang, Nadia A. Lanman, William C. Skarnes, Yang Yang
bioRxiv 2021.02.02.429384; doi: https://doi.org/10.1101/2021.02.02.429384
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Severe deficiency of voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice
Jingliang Zhang, Xiaoling Chen, Muriel Eaton, Shirong Lai, Anthony Park, Talha S. Ahmad, Jiaxiang Wu, Zhixiong Ma, Zhefu Que, Ji Hea Lee, Tiange Xiao, Yuansong Li, Yujia Wang, Maria I. Olivero-Acosta, James A. Schaber, Krishna Jayant, Zhuo Huang, Nadia A. Lanman, William C. Skarnes, Yang Yang
bioRxiv 2021.02.02.429384; doi: https://doi.org/10.1101/2021.02.02.429384

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