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

By 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

Posted 02 Feb 2021
bioRxiv DOI: 10.1101/2021.02.02.429384

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.

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