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

Jingliang Zhang; Xiaoling Chen; Muriel Eaton; Jiaxiang Wu; Zhixiong Ma; Shirong Lai; Anthony Park; Talha S Ahmad; Zhefu Que; Ji Hea Lee; Tiange Xiao; Yuansong Li; Yujia Wang; Maria I Olivero-Acosta; James A Schaber; Krishna Jayant; Chongli Yuan; Zhuo Huang; Nadia A Lanman; William C Skarnes; Yang Yang

doi:10.1016/j.celrep.2021.109495

Severe deficiency of the voltage-gated sodium channel Na_V1.2 elevates neuronal excitability in adult mice

Cell Rep. 2021 Aug 3;36(5):109495. doi: 10.1016/j.celrep.2021.109495.

Authors

Jingliang Zhang¹, Xiaoling Chen², Muriel Eaton¹, Jiaxiang Wu¹, Zhixiong Ma¹, Shirong Lai¹, Anthony Park¹, Talha S Ahmad¹, Zhefu Que¹, Ji Hea Lee¹, Tiange Xiao¹, Yuansong Li¹, Yujia Wang¹, Maria I Olivero-Acosta¹, James A Schaber³, Krishna Jayant⁴, Chongli Yuan⁵, Zhuo Huang⁶, Nadia A Lanman⁷, William C Skarnes⁸, Yang Yang⁹

Affiliations

¹ 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.
² 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.
³ Bioscience Imaging Facility, Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA.
⁴ Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA.
⁵ Davidson School of Chemical Engineering, Purdue University, West Lafayette, IN 47907, USA.
⁶ Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
⁷ Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
⁸ The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
⁹ 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.

Abstract

Scn2a encodes the voltage-gated sodium channel Na_V1.2, a main mediator of neuronal action potential firing. The current paradigm suggests that Na_V1.2 gain-of-function variants enhance neuronal excitability, resulting in epilepsy, whereas Na_V1.2 deficiency impairs neuronal excitability, contributing to autism. However, this paradigm does not explain why ∼20%-30% of individuals with Na_V1.2 deficiency still develop seizures. Here, we report the counterintuitive finding that severe Na_V1.2 deficiency results in increased neuronal excitability. Using a Na_V1.2-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_V1.1. Correspondingly, K_V channel openers alleviate the hyperexcitability of Na_V1.2-deficient neurons. This unexpected neuronal hyperexcitability may serve as a cellular basis underlying Na_V1.2 deficiency-related seizures.

Keywords: K(V)1.1; Na(V)1.2; SCN2A/Scn2a; epilepsy; gene trap; neuronal excitability; potassium channel; voltage-gated sodium channel.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Action Potentials
Aging / physiology*
Animals
Down-Regulation
Ion Channel Gating
Mice
Mice, Inbred C57BL
NAV1.2 Voltage-Gated Sodium Channel / deficiency*
NAV1.2 Voltage-Gated Sodium Channel / metabolism
Neurons / physiology*
Potassium Channels / metabolism

Substances

NAV1.2 Voltage-Gated Sodium Channel
Potassium Channels

Abstract

Publication types

MeSH terms

Substances

Grants and funding