Kv4.2 ^V404M Mutation Induces Epileptiform Activity and Multiple Behavioral Abnormalities in Heterozygous Knock-in Mice

The <i>KCND2</i> gene encodes the Kv4.2 voltage-gated potassium channel alpha subunit that underlies the somatodendritic subthreshold A-type current (I_SA) important for membrane excitability and dendritic signal integration and processing. A heterozygous missense mutation in <i>KCND2</i> (NM_012281.2: c.1210G>A) was identified in patients with early-onset epilepsy, autism, and global developmental delay, producing a conservative replacement of valine 404 to methionine (Lee et al., 2014; Zhang et al., 2021). To investigate the potential pathological role of the Kv4.2^V404M mutation, we generated Kv4.2^(V404M/+) heterozygous knock-in C57BL/6J mice using CRISPR technology and compared features of development, physiology, and behavior of Kv4.2^(V404M/+) mice to age- and sex-matched wild-type (Kv4.2^(+/+)) littermate controls. Kv4.2^(V404M/+) mice exhibit significant mortality during early development (>50%), poor reproductive behavior, decreased body weight of males (25-30%), altered I_SA functional properties, and 4-5 Hz spike-wave epileptiform discharges. These discharges occur frequently during periods of inactivity, with over 80% occurring during nonrapid eye movement sleep. ΔFosB was found to be significantly elevated in the cortex and hippocampus of Kv4.2^(V404M/+) mice. A combination of home-cage measurements and behavioral assays reveals that Kv4.2^(V404M/+) mice exhibit significant alterations in exploratory behavior, social interaction, fear conditioning, and spatial memory. Our results indicate that the Kv4.2^V404M mutation is sufficient to produce a dominant spectrum of physiological and behavioral changes in mice that likely have important implications for understanding the etiology and potential therapeutic approaches for this human channelopathy.