Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice

Abstract

Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including epilepsy. ANK2, which encodes a neuronal scaffolding protein, is frequently mutated in ASD, but its in vivo functions and disease-related mechanisms are largely unknown. Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and juvenile seizure-related death. Ank2-cKO cortical neurons show abnormally increased excitability and firing rate. These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment. Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice. These results suggest that Ank2 regulates neuronal excitability by regulating the length of and Kv7 density in the AIS and that Kv7 channelopathy is involved in Ank2-related brain dysfunctions.

Chemistry and bioactivity of lindenane sesquiterpenoids and their oligomers

“…In addition to the above-mentioned activities, LSs have also been reported to inhibit potassium ions, regulate metabolism, and analgesic activities. The abnormal function of potassium channels has been implicated in atrial fibrillation, 226 epilepsy, 227 and Alzheimer's disease, 228,229 and the effects of LSs on potassium channels have been discovered in recent years. Chlorahololides A ( 188 ) and B ( 229 ) exhibited potent inhibition on the delayed rectifier K + current, suggesting that LS can regulate body homeostasis by inhibiting K + efflux.…”