Heterozygous loss of epilepsy geneKCNQ2alters social, repetitive and exploratory behaviors

Abstract

KCNQ/K v 7 channels conduct voltage-dependent outward potassium currents that potently decrease neuronal excitability. Heterozygous inherited mutations in their principle subunits K v 7.2/KCNQ2 and K v 7.3/KCNQ3 cause benign familial neonatal epilepsy whereas patients with de novo heterozygous K v 7.2 mutations are associated with early-onset epileptic encephalopathy and neurodevelopmental disorders characterized by intellectual disability, developmental delay and autism. However, the role of K v 7.2-containing K v 7 channels in behaviors especially autism-associated behaviors has not been described. Because pathogenic K v 7.2 mutations in patients are typically heterozygous loss-of-function mutations, we investigated the contributions of K v 7.2 to exploratory, social, repetitive and compulsive-like behaviors by behavioral phenotyping of both male and female KCNQ2 +/− mice that were heterozygous null for the KCNQ2 gene. Compared with their wild-type littermates, male and female KCNQ2 +/− mice displayed increased locomotor activity in their home cage during the light phase but not the dark phase and showed no difference in motor coordination, suggesting hyperactivity during the inactive light phase. In the dark phase, KCNQ2 +/− group showed enhanced exploratory behaviors, and repetitive grooming but decreased sociability with sex differences in the degree of these behaviors. While male KCNQ2 +/− mice displayed enhanced compulsive-like behavior and social dominance, female KCNQ2 +/− mice did not. In addition to elevated seizure susceptibility, our findings together indicate that heterozygous loss of K v 7.2 induces behavioral abnormalities including autism-associated behaviors such as reduced sociability and enhanced repetitive behaviors. Therefore, our study is the first to provide a tangible link between loss-of-function K v 7.2 mutations and the behavioral comorbidities of K v 7.2-associated epilepsy.

The Role of Kv7 Channels in Neural Plasticity and Behavior

“…However, heterozygous KCNQ2 knock-out mice are viable and display increased locomotor activity and exploratory behavior ( Kim et al, 2020 ), consistent with behavioral hyperactivity induced by transgenic suppression of K v 7 currents ( Peters et al, 2005 ) and amphetamine and XE991 ( Sotty et al, 2009 ). These mice also show decreased sociability and increased repetitive and compulsive behavior ( Kim et al, 2020 ), reminiscent of autism seen in some EE patients with dominant KCNQ2 mutations ( Weckhuysen et al, 2012 , 2013 ; Milh et al, 2013 ). However, the precise circuitries responsible for these abnormal behaviors remain unknown.…”

“…Behavioral phenotyping of the global or conditional homozygous KCNQ2 knock-out mice has not been possible due to their early postnatal lethality or premature death, respectively (Watanabe et al, 2000;Soh et al, 2014). However, heterozygous KCNQ2 knock-out mice are viable and display increased locomotor activity and exploratory behavior (Kim et al, 2020), consistent with behavioral hyperactivity induced by transgenic suppression of K v 7 currents (Peters et al, 2005) and amphetamine and XE991 (Sotty et al, 2009). These mice also show decreased sociability and increased repetitive and compulsive behavior (Kim et al, 2020), reminiscent of autism seen in some EE patients with dominant KCNQ2 mutations (Weckhuysen et al, 2012(Weckhuysen et al, , 2013Milh et al, 2013).…”

The Role of Kv7.2 in Neurodevelopment: Insights and Gaps in Our Understanding

“…The focus of these earlier studies was mainly on seizure susceptibility, as Kv7.2 was not linked yet to behavioral abnormalities. With the current evidence that the Kv7.2 channel plays a role in neurodevelopment and that variants in KCNQ2 are enriched in ASD cohorts, the KCNQ2 KO model was also subjected to extensive behavioral analysis; an in-depth behavioral study, indeed, recently showed autismassociated behaviors such as a decrease in social behavior and enhanced repetitive behaviors in KCNQ2 heterozygous KO mice (Kim et al, 2020).…”

KCNQ2 encephalopathy manifesting with Rett-like features

“…The role of Kv7.2 dysfunction in the expression of abnormal GABAergic parvalbumin-positive interneurons and their dendritic arborization within corticostriatal and nigrostriatal dopaminergic transmission (an impairment also described in Mecp2-null mice) could suggest a possible link between Rett syndrome, KCNQ2 encephalopathy, and other neuropsychiatric disorders in terms of the pathophysiology of hypokinetic movement disorders, dystonia, and hand stereotypies. 7 Recent experimental data on KCNQ2+/− mice established a link between loss-of-function Kv7.2 mutations and behavioral disorders that was characterized by increased repetitive and compulsive behaviors, reduced social interest, and impaired social interaction mechanisms. 7 …”

“… 7 Recent experimental data on KCNQ2+/− mice established a link between loss-of-function Kv7.2 mutations and behavioral disorders that was characterized by increased repetitive and compulsive behaviors, reduced social interest, and impaired social interaction mechanisms. 7 …”