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

Zhang, J.; Chen, X.; Eaton, M.; Lai, S.; Park, A.; Ahmad, T. S.; Wu, J.; Ma, Z.; Que, Z.; Hea Lee, J.; Xiao, T.; Li, Y.; Wang, Y.; Olivero-Acosta, M. I.; Schaber, J. A.; Jayant, K.; Huang, Z.; Lanman, N. A.; Skarnes, W. C.; Yang, Y.

doi:10.1101/2021.02.02.429384

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bioRxiv · 10.1101/2021.02.02.429384

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

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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. TEASERSevere NaV1.2 deficiency results in neuronal hyperexcitability via the compensatory downregulation of potassium channels. HIGHLIGHTSO_LISevere NaV1.2 deficiency results in enhanced excitability of medium spiny neurons (MSNs) and pyramidal neurons in adult mice; C_LIO_LIIncreased neuronal excitability in MSNs is accompanied by elevated voltage threshold; C_LIO_LINaV1.2 deficiency-related hyperexcitability is reversible with the restoration of Scn2a expression, and is autonomous; C_LIO_LIThe expression of the KV1.1 channel has a compensatory reduction in neurons with NaV1.2 deficiency, and KV channels openers normalize the neuronal excitability; C_LIO_LIThe enhanced excitability in brain slices translates to elevated in vivo firing commonly associated with seizures. C_LI

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Zhang, J., Chen, X., Eaton, M., Lai, S., Park, A., Ahmad, T. S., Wu, J., Ma, Z., Que, Z., Hea Lee, J., Xiao, T., Li, Y., Wang, Y., Olivero-Acosta, M. I., Schaber, J. A., Jayant, K., Huang, Z., Lanman, N. A., Skarnes, W. C., Yang, Y.. 2021-02-02. Severe deficiency of voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice. https://doi.org/10.1101/2021.02.02.429384

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