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BK channel β4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures

Nature Neuroscience volume 8, pages 17521759 (2005) | Download Citation

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Abstract

Synaptic inhibition within the hippocampus dentate gyrus serves a 'low-pass filtering' function that protects against hyperexcitability that leads to temporal lobe seizures. Here we demonstrate that calcium-activated potassium (BK) channel accessory β4 subunits serve as key regulators of intrinsic firing properties that contribute to the low-pass filtering function of dentate granule cells. Notably, a critical β4 subunit function is to preclude BK channels from contributing to membrane repolarization and thereby broaden action potentials. Longer-duration action potentials secondarily recruit SK channels, leading to greater spike frequency adaptation and reduced firing rates. In contrast, granule cells from β4 knockout mice show a gain-of-function for BK channels that sharpens action potentials and supports higher firing rates. Consistent with breakdown of the dentate filter, β4 knockouts show distinctive seizures emanating from the temporal cortex, demonstrating a unique nonsynaptic mechanism for gate control of hippocampal synchronization leading to temporal lobe epilepsy.

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Acknowledgements

We thank S. Wiler for technical assistance and B.S. Rothberg for critical reading of the manuscript. This work was supported by US National Institutes of Health grants NS29709 and HD24064 to J.L.N., American Heart Association grant 02250724 to Q.H.C. and a University of Texas Health Science Center Executive Research Committee grant to R.B. R.W.A. is an investigator with the Howard Hughes Medical Institute.

Author information

Author notes

    • Robert Brenner
    •  & Qing H Chen

    These authors contributed equally to this manuscript.

Affiliations

  1. Department of Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78229, USA.

    • Robert Brenner
    • , Qing H Chen
    •  & Glenn M Toney
  2. Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

    • Alex Vilaythong
    •  & Jeffrey L Noebels
  3. Howard Hughes Medical Institute, Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.

    • Richard W Aldrich

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Robert Brenner or Richard W Aldrich.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Tissue distribution of β4 gene expression.

  2. 2.

    Supplementary Fig. 2

    Effect of SK channel block on firing properties during a 300 pA, 900 ms current injection utilizing UCL1684.

Videos

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    Supplementary Video 1

    Spontaneous limbic seizure in BK β4−/− mouse.

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DOI

https://doi.org/10.1038/nn1573

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