Abstract Background Autism spectrum disorder (ASD) and epilepsy are highly comorbid, suggesting potential overlap in genetic etiology, pathophysiology, and neurodevelopmental abnormalities; however, the nature of this relationship remains unclear. This work investigated how two ion channel mutations, one associated with autism (Scn2a‐null) and one with epilepsy (Kcna1‐null), interact to modify genotype–phenotype relationships in the context of autism. Previous studies have shown that Scn2a+/– ameliorates epilepsy in Kcna1–/– mice, improving survival, seizure characteristics, and brain–heart dynamics. Here, we tested the converse, whether Kcna1 deletion modifies ASD‐like repetitive and social behaviors in Scn2a+/– mice. Methods Mice were bred with various combinations of Kcna1 and Scn2a knockout alleles. Animals were assessed for repetitive behaviors using marble burying, grooming, and nestlet shredding tests and for social behaviors using sociability and social novelty preference tests. Results Behavioral testing revealed drastic reductions in all repetitive behaviors in epileptic Kcna1–/– mice, but relatively normal social interactions. In contrast, mice with partial Kcna1 deletion (Kcna1+/–) exhibited increased self‐grooming and decreased sociability suggestive of ASD‐like features similar to those observed in Scn2a+/– mice. In double‐mutant Scn2a+/–; Kcna1+/– mice, the two mutations interacted to partially normalize ASD‐like behaviors associated with each mutation independently. Conclusions Taken together, these findings suggest that Kv1.1 subunits are important in pathways and neural networks underlying ASD and that Kcna1 may be a therapeutic target for treatment of Scn2a‐associated ASD.
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