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Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy

Nature Neuroscience volume 13, pages 1056–1058 (2010)Cite this article

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Abstract

We found the voltage-gated K+ channel Kv12.2 to be a potent regulator of excitability in hippocampal pyramidal neurons. Genetic deletion and pharmacologic block of Kv12.2 substantially reduced the firing threshold of these neurons. Kv12.2−/− (also known as Kcnh3−/−) mice showed signs of persistent neuronal hyperexcitability including frequent interictal spiking, spontaneous seizures and increased sensitivity to the chemoconvulsant pentylenetetrazol.

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Figure 1: Kv12.2−/− neurons are hyperexcitable.
Figure 2: Pharmacological block of Kv12.2 increases neuronal excitability.
Figure 3: Kv12.2−/− seizure phenotypes.

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Acknowledgements

Lentivirus vectors were kindly provided by A. Maximov. The project was funded by the Genomics Institute of the Novartis Research Foundation, US National Institute of Neurological Disorders and Stroke grants awarded to T.J. and J.N., an American Heart Association fellowship supporting X.Z. and INSERM funds supporting F.B.

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Author notes

  1. Xiaofei Zhang, Federica Bertaso & Timothy Jegla

    Present address: Present addresses: Sanford-Burnham Medical Research Institute, La Jolla, California, USA (X.Z.), Institut de Génomique Fonctionnelle, Université de Montpellier, Montpellier, France (F.B.), and Department of Biology and Huck Institute for Life Sciences, Pennsylvania State University, University Park, Pennsylvania, USA (T.J.).,

  2. Xiaofei Zhang and Federica Bertaso: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA

    Xiaofei Zhang, Federica Bertaso, Karsten Baumgärtel, Sinead M Clancy & Timothy Jegla

  2. Department of Neurology, Baylor College of Medicine, Houston, Texas, USA

    Jong W Yoo & Jeffrey Noebels

  3. Genomics Institute of the Novartis Research Foundation, San Diego, California, USA

    Van Lee, Cynthia Cienfuegos, Carly Wilmot, Jacqueline Avis, Truc Hunyh, Catherine Daguia & Christian Schmedt

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Contributions

V.L., C.C., C.W., J.A., T.J. and C.S. designed targeting constructs, handled embryonic stem cell work and produced germ-line chimaeras. X.Z. and F.B. established the Kv12.2−/− mouse line, S.M.C. analyzed Kv12.2 expression, and J.W.Y. and J.N. provided EEG analysis. X.Z. and F.B. conducted patch clamp experiments and contributed to manuscript preparation, X.Z., F.B. and K.B. conducted behavioral experiments. T.H., C.D., S.M.C. and T.J. designed the screen for Kv12.2 inhibitors and identified and characterized CX4. T.J. supervised the project, analyzed data and wrote the manuscript.

Corresponding author

Correspondence to Timothy Jegla.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Methods and Supplementary Sequences (PDF 2367 kb)

Supplementary Video 1

Video and EEG recording of a seizure in an awake, behaving Kv12.2−/− mouse. (MOV 2532 kb)

Supplementary Sequences

Sequences used in phylogenetic analysis in FASTA format. (TXT 15 kb)

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Zhang, X., Bertaso, F., Yoo, J. et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nat Neurosci 13, 1056–1058 (2010). https://doi.org/10.1038/nn.2610

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