Author(s): Sophie Hill, University of Michigan; Sophie Hill, University of Michigan; Paymaan Jafar-Nejad, Ionis Pharmaceuticals; Frank Rigo, Ionis Pharmaceuticals; Miriam Meisler, University of Michigan //

ABSTRACT: The neuronal voltage-gated sodium channel Nav1.6 is concentrated at the axon initial segment (AIS), where it plays a key role in initiation of action potentials. Gain-of-function mutations in SCN8A are a cause of developmental and epileptic encephalopathy (DEE). Administration of an antisense oligonucleotide (ASO) that reduces expression of Scn8a results in delayed seizure onset in a mouse model of Scn8a DEE. We previously showed interaction of Scn8a expression with the Scn1a gene (Lenk et al, Ann. Neurol. 87:339-346, 2020).  We then asked whether reduction of Scn8a expression could ameliorate the seizure phenotypes of mice with inactivation of Kcna1, which encodes a voltage-gated potassium channel that is also localized at the AIS. Kcna1 null mice have spontaneous seizures and premature death (Smart et al, 1998 Neuron). Homozygous Kcna1 null mice were treated on postnatal day 2 by intracerebroventricular injection of the Scn8a ASO. Surviving mice were given repeated doses of the ASO at four week intervals. Treatment with the Scn8a ASO rescued premature death in the Kcna1 null mice. This work demonstrates a novel genetic interaction between two ion channels expressed at the axon initial segment.

Source of Funding: NINDS R01 NS34509