Kv1.1 deficiency alters repetitive and social behaviors in mice and rescues autistic‐like behaviors due to Scn2a haploinsufficiency

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.

Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2aK1422E mice

“…This is similar to what has been reported in Scn2a +/mice (Léna and Mantegazza, 2019;Spratt et al, 2019;Tatsukawa et al, 2019). Scn2a E/+ mice also displayed hyper-social behavior in a three-chamber assay, while inconsistent effects on social behavior have been reported in Scn2a +/mice (Tatsukawa et al, 2019;Indumathy et al, 2021). Although ASD is typically associated with social behavior deficits (Barak and Feng, 2016), hyper-social behavior has been reported in other ASD-associated genetic mouse models (Chao et al, 2010;Mejias et al, 2011).…”

“…knockout models have been used to study phenotypes associated with LoF effects on NaV1.2 (Léna and Mantegazza, 2019;Spratt et al, 2019;Tatsukawa et al, 2019;Indumathy et al, 2021).…”

Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2a K1422E mice

“…Similar reductions in anxiety-like behavior and marble burying have been reported in Scn2a +/− mice by some groups, although the opposite effect has also been reported ( 9 , 32 , 33 , 87 ). Scn2a E/+ mice also displayed hyper-social behavior in a three-chamber assay, while inconsistent effects on social behavior have been reported in Scn2a +/− mice ( 33 , 40 , 88 , 89 ). Although ASD is typically associated with social behavior deficits ( 35 ), hyper-social behaviors such as inappropriate social approach and enhanced direct social interaction have been reported in ASD-associated genetic mouse models including Scn2a ( 40 , 88 , 90 , 91 ).…”

Gene expression profiling in trigeminal ganglia from Cntnap2-/-and Shank3b-/-mouse models of autism spectrum disorder

“…Another noteworthy result is the downregulation of Kcna1 in Shank3b -/- adult TG which encodes for the Kv1.1 voltage-gated potassium channel subunits that regulate axonal excitability and whose loss of function missense mutations are often associated with ataxia and epilepsy (Thouta et al, 2021). Kcna -/- mice have been shown to demonstrate normal sociability and reduced repetitive behaviors as compared to WT counterparts (Indumathy et al, 2021). These results, suggesting an increased excitability in both Shank3b and Cntnap2 models, seem to conflict with our findings on inhibitory markers.…”