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Research ArticleNeuropharmacology

Dysfunction of Extrasynaptic GABAergic Transmission in Phospholipase C-Related, but Catalytically Inactive Protein 1 Knockout Mice Is Associated with an Epilepsy Phenotype

Gang Zhu, Shukuko Yoshida, Keisuke Migita, Junko Yamada, Fumiaki Mori, Masahiko Tomiyama, Koichi Wakabayashi, Takashi Kanematsu, Masato Hirata, Sunao Kaneko, Shinya Ueno and Motohiro Okada
Journal of Pharmacology and Experimental Therapeutics March 2012, 340 (3) 520-528; DOI: https://doi.org/10.1124/jpet.111.182386
Gang Zhu
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Shukuko Yoshida
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Keisuke Migita
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Junko Yamada
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Fumiaki Mori
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Masahiko Tomiyama
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Koichi Wakabayashi
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Takashi Kanematsu
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Masato Hirata
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Sunao Kaneko
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Shinya Ueno
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Motohiro Okada
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Abstract

Phospholipase C-related, but catalytically inactive protein (PRIP) was first identified as a novel inositol 1,4,5-triphosphate binding protein. The PRIP-1 subtype is expressed predominantly in the central nervous system and binds directly to the GABA type A receptor (GABAA-R) β-subunit and several other proteins involved in the trafficking of GABAA-Rs to the plasma membrane. We found that the PRIP-1 knockout mouse showed an epileptic phenotype, confirmed by electroencephalogram. These ictal seizures were completely suppressed by diazepam (DZP), but the interictal discharges could not be abolished. We studied the electrophysiological properties of GABAergic transmission in hippocampal CA1 pyramidal neurons, using a slice patch-clamp technique. There was no difference in the effect of up to 1 μM DZP on the amplitude and frequency of miniature inhibitory postsynaptic currents between PRIP-1 knockout neurons versus wild-type neurons. In contrast, the amplitude of the tonic GABA current in PRIP-1 knockout neurons was markedly reduced compared with that in wild-type neurons. Consequently, the effect of DZP on PRIP-1 knockout mice was reduced. Dysfunction of extrasynaptic GABAergic transmission probably is involved in the epileptic phenotype of PRIP-1 knockout mice.

Footnotes

  • This work was supported in part by a Grant for Priority Research designated by the President of Hirosaki University; Grants-in-Aid for Scientific Research (S) [Grant 16109006]; Grants-in-Aid for Scientific Research (A) [Grant 18209035]; Grants-in-Aid for Scientific Research (B) [Grants 18300137, 18390316]; Grants-in-Aid for Scientific Research (C) [Grants 17590856, 20591361]; and Grants-in-Aid for Exploratory Research [Grants 1659272, 18659455], all provided by the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.182386.

  • ABBREVIATIONS:

    PRIP
    phospholipase C-related, but catalytically inactive protein
    DZP
    diazepam
    GABAA-R
    GABA type A receptor
    GABARAP
    GABAA-R-associated protein
    KO
    knockout
    BZP
    benzodiazepine
    BMI
    bicuculline methiodide
    EEG
    electroencephalogram
    MES
    maximal electroshock
    ACSF
    artificial cerebrospinal fluid
    mIPSC
    miniature inhibitory postsynaptic current
    PCR
    polymerase chain reaction
    PBST
    0.05% Tween 20 in phosphate-buffered saline
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    WT
    wild type
    CGP55845
    (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl](phenylmethyl)phosphinic acid hydrochloride.

  • Received April 9, 2011.
  • Accepted November 28, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 3
1 Mar 2012
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Research ArticleNeuropharmacology

PRIP-l in Regulation of Extrasynaptic GABAA-Rs

Gang Zhu, Shukuko Yoshida, Keisuke Migita, Junko Yamada, Fumiaki Mori, Masahiko Tomiyama, Koichi Wakabayashi, Takashi Kanematsu, Masato Hirata, Sunao Kaneko, Shinya Ueno and Motohiro Okada
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 520-528; DOI: https://doi.org/10.1124/jpet.111.182386

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Research ArticleNeuropharmacology

PRIP-l in Regulation of Extrasynaptic GABAA-Rs

Gang Zhu, Shukuko Yoshida, Keisuke Migita, Junko Yamada, Fumiaki Mori, Masahiko Tomiyama, Koichi Wakabayashi, Takashi Kanematsu, Masato Hirata, Sunao Kaneko, Shinya Ueno and Motohiro Okada
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 520-528; DOI: https://doi.org/10.1124/jpet.111.182386
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