Abstracts

Rationale: The neuronal sodium channel Na_v1.6 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, and this ASO also rescues survival of Dravet mice with mutation of Scn1a (Lenk et al, Ann. Neurol. 87:339-346, 2020). We asked whether reduction of Scn8a expression could ameliorate the seizure phenotypes of mice with mutations in two genes encoding potassium channels that are also localized at the AIS: Kcnq2 and Kcna1. The effect of Scn8a reduction on mutation of the synaptic protein LGI1 was also examined.

Methods: Mice with homozygous mutations of Kcna1 (Smart et al Neuron 1998), Kcnq2 (Soh et al, J. Neurosci. 34:5311-5321, 2014) and Lgi1 (Chambrol et al, Brain 133:2749-2762) were treated on postnatal day 2 by intracerebroventricular injection of the ASO that reduces the level of Scn8a transcript by 50%. The number of convulsive seizures and length of survival were monitored.

Results: In the Kcna1 and Kcnq2 mutant mice, treatment with the Scn8a ASO resulted in significant increase in the age at which seizures began, as well as the length of survival. In contrast, in the Lgi1 mutant mice, there was a shorter increase in length of survival.

Conclusions: The data demonstrate that the severity of genetically determined seizure disorders can be modified by compensatory changes among ion channels co-localized at the AIS. An ASO targeting SCN8A may therefore have therapeutic value in multiple types of genetic epilepsy.

Funding: Please list any funding that was received in support of this abstract.: Supported by NINDS R01 NS34509.