A missense mutation in Kcnc3 causes hippocampal learning deficits in mice

Abstract

Although a wide variety of genetic tools has been developed to study learning and memory, the molecular basis of memory encoding remains incompletely understood. Here, we undertook an unbiased approach to identify novel genes critical for memory encoding. From a large-scale, in vivo mutagenesis screen using contextual fear conditioning, we isolated in mice a mutant, named Clueless , with spatial learning deficits. A causative missense mutation (G434V) was found in the voltage-gated potassium channel, subfamily C member 3 ( Kcnc3) gene in a region that encodes a transmembrane voltage sensor. Generation of a Kcnc3 G434V CRISPR mutant mouse confirmed this mutation as the cause of the learning defects. While G434V had no effect on transcription, translation, or trafficking of the channel, electrophysiological analysis of the G434V mutant channel revealed a complete loss of voltage-gated conductance, a broadening of the action potential, and decreased neuronal firing. Together, our findings have revealed a role for Kcnc3 in learning and memory.

Transcriptomics reveals age-related changes in ion transport–related factors in yak lungs

“…The FOXP family proteins were also found to regulate KCNC3, KCNQ3, SLC12A4, SLC4A9, and TRPM2. KCNC3, KCNQ3, and KCNMA1 are voltage-gated potassium ion channel proteins, and the downregulation of KCNC3 and KCNQ3 in yak lungs suggested that the expression of voltage-gated potassium ion channels decreases in yaks with age, reducing membrane depolarization and harmful effects of pulmonary edema ( 29 , 30 ). KCNMA1 upregulation might be associated with its role in promoting vascular endothelial cell growth ( 31 , 32 ).…”