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

doi:10.1073/pnas.2204901119

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

Neurology

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English (US)
Article number	e2204901119
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	119
Issue number	31
DOIs	https://doi.org/10.1073/pnas.2204901119
State	Published - Aug 2 2022

Funding

ACKNOWLEDGMENTS. We thank Drs. Youxing Jiang and Jiangtao Guo for predicting the structure of KCNC3 G434V, and Kim Brown and Lisa Thomas for behavior tests. We also thank Dr. Kimberly Cox at Efferent Manuscript Services for her assistance in preparing the manuscript for publication. Mouse production was performed at the UTSW Transgenic Core.Exome sequencing and sequencing data analysis were performed at the McDermott Center Next-Generation Sequencing Core at UT Southwestern Medical Center. This work was supported by NIH Grant U01MH61915 to J.S.T. and Brain Behavior Research Foundation Young Investigator Grant 29767 to C.L. J.S. T. and E.R. K. are investigators in the HHMI.

Keywords

ENU mutagenesis
behavioral screen
hippocampus
learning and memory
potassium channels

ASJC Scopus subject areas

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Xu, P., Shimomura, K., Lee, C., Gao, X., Simpson, E. H., Huang, G., Joseph, C. M., Kumar, V., Ge, W. P., Pawlowski, K. S., Frye, M. D., Kourrich, S., Kandel, E. R., & Takahashi, J. S. (2022). A missense mutation in Kcnc3 causes hippocampal learning deficits in mice. Proceedings of the National Academy of Sciences of the United States of America, 119(31), Article e2204901119. https://doi.org/10.1073/pnas.2204901119

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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 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.",

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author = "Pin Xu and Kazuhiro Shimomura and Changhoon Lee and Xiaofei Gao and Simpson, {Eleanor H.} and Guocun Huang and Joseph, {Chryshanthi M.} and Vivek Kumar and Ge, {Woo Ping} and Pawlowski, {Karen S.} and Frye, {Mitchell D.} and Sa{\"i}d Kourrich and Kandel, {Eric R.} and Takahashi, {Joseph S.}",

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Xu, P, Shimomura, K, Lee, C, Gao, X, Simpson, EH, Huang, G, Joseph, CM, Kumar, V, Ge, WP, Pawlowski, KS, Frye, MD, Kourrich, S, Kandel, ER & Takahashi, JS 2022, 'A missense mutation in Kcnc3 causes hippocampal learning deficits in mice', Proceedings of the National Academy of Sciences of the United States of America, vol. 119, no. 31, e2204901119. https://doi.org/10.1073/pnas.2204901119

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T1 - A missense mutation in Kcnc3 causes hippocampal learning deficits in mice

AU - Xu, Pin

AU - Shimomura, Kazuhiro

AU - Lee, Changhoon

AU - Gao, Xiaofei

AU - Simpson, Eleanor H.

AU - Huang, Guocun

AU - Joseph, Chryshanthi M.

AU - Kumar, Vivek

AU - Ge, Woo Ping

AU - Pawlowski, Karen S.

AU - Frye, Mitchell D.

AU - Kourrich, Saïd

AU - Kandel, Eric R.

AU - Takahashi, Joseph S.

PY - 2022/8/2

Y1 - 2022/8/2

N2 - 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.

AB - 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.

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A missense mutation in Kcnc3 causes hippocampal learning deficits in mice

Abstract

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