A missense mutation in Kcnc3 causes hippocampal learning deficits in mice.

Proceedings of the National Academy of Sciences of the United States of America 2022 Aug 02

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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 Kcnc3G434V 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.

Citation

Pin Xu, Kazuhiro Shimomura, Changhoon Lee, Xiaofei Gao, Eleanor H Simpson, Guocun Huang, Chryshanthi M Joseph, Vivek Kumar, Woo-Ping Ge, Karen S Pawlowski, Mitchell D Frye, Saïd Kourrich, Eric R Kandel, Joseph S Takahashi. A missense mutation in Kcnc3 causes hippocampal learning deficits in mice. Proceedings of the National Academy of Sciences of the United States of America. 2022 Aug 02;119(31):e2204901119