A missense mutation in Kcnc3 causes hippocampal learning deficits in mice

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbere2204901119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number31
StatePublished - Aug 2 2022


  • ENU mutagenesis
  • behavioral screen
  • hippocampus
  • learning and memory
  • potassium channels

ASJC Scopus subject areas

  • General


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