Heterozygous loss of epilepsy gene KCNQ2 alters 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.

Keywords: KCNQ2; Kv7 channels; anxiety; epilepsy; excitability; locomotion; seizures; social dominance; social interaction.