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

Scn2a encodes the voltage-gated sodium channel Na 1.2, a main mediator of neuronal action potential firing. The current paradigm suggests that Na 1.2 gain-of-function variants enhance neuronal excitability, resulting in epilepsy, whereas Na 1.2 deficiency impairs neuronal excitability, contributing...

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Bibliographic Details
Published in:	Cell reports (Cambridge) Vol. 36; no. 5; p. 109495
Main Authors:	Zhang, Jingliang, Chen, Xiaoling, Eaton, Muriel, Wu, Jiaxiang, Ma, Zhixiong, Lai, Shirong, Park, Anthony, Ahmad, Talha S, Que, Zhefu, Lee, Ji Hea, Xiao, Tiange, Li, Yuansong, Wang, Yujia, Olivero-Acosta, Maria I, Schaber, James A, Jayant, Krishna, Yuan, Chongli, Huang, Zhuo, Lanman, Nadia A, Skarnes, William C, Yang, Yang
Format:	Journal Article
Language:	English
Published:	United States 03-08-2021
Subjects:	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 K(V)1.1 epilepsy Na(V)1.2 SCN2A/Scn2a gene trap potassium channel voltage-gated sodium channel neuronal excitability
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Summary:	Scn2a encodes the voltage-gated sodium channel Na 1.2, a main mediator of neuronal action potential firing. The current paradigm suggests that Na 1.2 gain-of-function variants enhance neuronal excitability, resulting in epilepsy, whereas Na 1.2 deficiency impairs neuronal excitability, contributing to autism. However, this paradigm does not explain why ∼20%-30% of individuals with Na 1.2 deficiency still develop seizures. Here, we report the counterintuitive finding that severe Na 1.2 deficiency results in increased neuronal excitability. Using a Na 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 1.1. Correspondingly, K channel openers alleviate the hyperexcitability of Na 1.2-deficient neurons. This unexpected neuronal hyperexcitability may serve as a cellular basis underlying Na 1.2 deficiency-related seizures.
ISSN:	2211-1247