A Missense Mutation in Kcnc3 Causes Hippocampal Learning Deficits in Mice

Although a wide variety of genetic tools have 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 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 Kcnc3 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 previously unrecognized role for Kcnc3 in learning and memory. Overall design: Comparative gene expression profiling analysis of RNA-seq data (4 replicates) in the dorsal and ventral parts of DG and CA in mice hippocampus after contextual fear conditioning training