Abstracts

Rationale: Epilepsy and autism spectrum disorders (ASD) are highly comorbid, co-occurring in up to 30% of patients, which suggests a shared genetic etiology, underlying pathophysiology, and/or neurodevelopmental abnormalities; however, the exact nature of this relationship remains unclear. ASD are neurodevelopmental diseases diagnosed by three main types of abnormal behaviors: increased repetitive behavior, decreased social interaction, and impaired communication. Here, repetitive behaviors and social interactions were examined in the Kcna1 mouse model of epilepsy and the Scn2a mouse model of autism, as well as double mutant combinations. Kcna1 encodes voltage-gated Kv1.1 potassium channel alpha subunits, whereas Scn2a encodes voltage-gated Nav1.2 sodium channel alpha subunits. First, we evaluated whether epileptic Kcna1-null mice (Kcna1^–/–) exhibit autistic-like behaviors, making them a useful model for studying shared pathways and mechanisms of epilepsy and autism. Second, we tested whether the Kcna1-null mutation can act as a genetic modifier of ASD phenotypes in the Scn2a heterozygous knockout mouse (Scn2a^+/–), an accepted model of human autism.  Methods: To assess autistic-like behaviors, repetitive behaviors (marble burying, self-grooming, and nestlet shredding) and social interaction (sociability and social novelty) were measured in mice with various combinations of Kcna1 and Scn2a knockout alleles, as well as wild-type (WT) controls. For each genotype, 5-13 animals were tested. Statistical analyses were performed using GraphPad Prism version 7.  Results: Kcna1^–/– mice exhibited significantly decreased repetitive behaviors in tests of self-grooming (P=0.0003), marble burying (P=0.0033), and nestlet shredding (P=0.0002), but their social interactions were unaltered compared to WT. Scn2a^+/– mice displayed increased self-grooming (P=0.0087) and decreased marble burying (P=0.0007), but their nestlet shredding and social behavior was unchanged compared to WT. Complete genetic ablation of Kcna1 in Scn2a^+/– mice (i.e., Scn2a^+/–; Kcna1^–/–) led to decreased repetitive behaviors similar to single mutant Kcna1^–/– mice. In contrast, however, partial deletion of Kv1.1 potassium channels in Scn2a^+/– mice (i.e., Scn2a^+/–; Kcna1^+/–) had a selective therapeutic effect, normalizing self-grooming repetitive behavior to levels indistinguishable from WT (P=0.0166) while not significantly modifying other repetitive behaviors.  Conclusions: The decrease in repetitive behavior in Kcna1^–/– mice could be indicative of some degree of autistic behavior since Scn2a^+/– mice also showed decreased marble burying behavior; however, Scn2a^+/– mice exhibited increased self-grooming repetitive behavior as might be expected for an autism model. Another possibility is that the decreased repetitive behavior in Kcna1^–/– mice could represent a behavioral abnormality that opposes ASD. This idea is supported by the ability of partial Kcna1 deletion to act as a protective genetic modifier of the increased self-grooming autistic behavior in Scn2a^+/– mice. Funding: This work was supported by grants from the National Institutes of Health (R01NS100954 and R01NS099188).