期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：31
DOI：10.1073/pnas.2204901119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Using an unbiased genetic screen, we uncovered a novel missense mutation in the voltage-gated potassium channel, subfamily C member 3 gene (
Kcnc3) that decreases the activity of hippocampal neurons and causes defects in learning and memory in a fear-conditioning task. These findings provide evidence that
Kcnc3 is important for hippocampal encoding of memories and contribute significantly to our understanding of potassium currents in the hippocampus and their role in learning.
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.
关键词：enlearning and memorypotassium channelsbehavioral screenENU mutagenesishippocampus
