A mutation in the SCN2A gene associated with BFNIS leads to seizures and behavioral impairment in a mouse model

Aims: Voltage-gated sodium channels are essential to initiate action potentials in brain neurons. Mutations of the SCN2A gene encoding NaV1.2 are associated with benign familial neonatal infantile seizures (BFNIS) or severe epileptic encephalopathy. The aim of this study is to generate a mouse model of BFNIS caused by a mutation in the SCN2A gene to better understand the pathophysiology and to potentially develop new therapeutic strategies.

Methods: Recently, we identified a missense mutation in SCN2A (A263V). The patient carrying this mutation presented with neonatal onset, pharmaco-resistant seizures, and later onset variable episodes of ataxia, myoclonia, headache, and back pain after 18 months of age. Electrophysiological studies in a heterologous expression system indicated that this SCN2A mutation leads to an increase of the persistent sodium current revealing a pronounced NaV1.2 gain-of-function effect. We generated SCN2A knock-in mice carrying the human point mutation.

Results: Homozygous and heterozygous knock-in mice are lighter than their littermates. Seizures are observed in homozygous mice starting at 3 weeks. Behavioral studies in adult mice revealed hyperactivity and cognitive impairment being more pronounced in homozygous animals. Current-clamp experiments in acute brain slices indicated an increased frequency in action potential firing in hippocampal CA1 pyramidal neurons in heterozygous SCN2A mutant mice compared with their wild-type littermates.

Conclusion: These results suggest that an increased excitability of pyramidal neurons caused by a gain of function of the NaV1.2 channel underlies BFNIS. Other symptoms such as ataxia, myoclonus, or pain might be caused by similarly increased excitability in unmyelinated nerve fibers in which SCN2A is expressed later in development than in myelinated pyramidal neurons.