Spontaneous seizure and memory loss in mice expressing an epileptic encephalopathy variant in the calmodulin-binding domain of K v 7.2.

Epileptic encephalopathy (EE) is characterized by seizures that respond poorly to antiseizure drugs, psychomotor delay, and cognitive and behavioral impairments. One of the frequently mutated genes in EE is KCNQ2 , which encodes the K v 7.2 subunit of voltage-gated K v 7 potassium channels. K v 7 channels composed of K v 7.2 and K v 7.3 are enriched at the axonal surface, where they potently suppress neuronal excitability. Previously, we reported that the de novo dominant EE mutation M546V in human K v 7.2 blocks calmodulin binding to K v 7.2 and axonal surface expression of K v 7 channels via their intracellular retention. However, whether these pathogenic mechanisms underlie epileptic seizures and behavioral comorbidities remains unknown. Here, we report conditional transgenic c Kcnq2 +/M547V mice, in which expression of mouse K v 7.2-M547V (equivalent to human K v 7.2-M546V) is induced in forebrain excitatory pyramidal neurons and astrocytes. These mice display early mortality, spontaneous seizures, enhanced seizure susceptibility, memory impairment, and repetitive behaviors. Furthermore, hippocampal pathology shows widespread neurodegeneration and reactive astrocytes. This study demonstrates that the impairment in axonal surface expression of K v 7 channels is associated with epileptic seizures, cognitive and behavioral deficits, and neuronal loss in KCNQ2 -related EE.