Ectopic expression of the GABAA receptor a6 subunit in hippocampal pyramidal neurons produces extrasynaptic receptors and an increased tonic inhibition.

William Wisden, D. Cope, T. Klausberger, B. Hauer, S. T. Sinkkonen, V. Tretter, R. Lujan, A. Jones, E. R. Korpi, I. Mody, W. Sieghart, P. Somogyi

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    Abstract

    We generated transgenic (Thy1alpha6) mice in which the GABA(A) receptor alpha6 subunit, whose expression is usually confined to granule cells of cerebellum and cochlear nuclei, is ectopically expressed under the control of the pan-neuronal Thy-1.2 promoter. Strong Thy1alpha6 subunit expression occurs, for example, in deep cerebellar nuclei, layer V iscocortical and hippocampal pyramidal cells and dentate granule cells. Ligand binding and protein biochemistry show that most forebrain alpha6 subunits assemble as alpha6betagamma2-type receptors, and some as alpha1alpha6betagamma2 and alpha3alpha6betagamma2 receptors. Electron microscopic immunogold labeling shows that most Thy1-derived alpha6 immunoreactivity is in the extrasynaptic plasma membrane of dendrites and spines in both layer V isocortical and CA1pyramidal cells. Synaptic immunolabeling is rare. Consistent with the alpha6 subunits' extrasynaptic localization, Thy1alpha6 CA1 pyramidal neurons have a five-fold increased tonic GABA(A) receptor-mediated current compared with wild-type cells; however, the spontaneous IPSC frequency and the mIPSC amplitude in Thy1alpha6 mice decrease 37 and 30%, respectively compared with wild-type, Our results strengthen the idea that GABA(A) receptors containing alpha6 subunits can function as extrasynaptic receptors responsible for tonic inhibition and further suggest that a homeostatic mechanism might operate, whereby increased tonic inhibition causes a compensatory decrease in synaptic GABA(A) receptor responses. (C) 2002 Elsevier Science Ltd. All rights reserved.

    Original languageEnglish
    Pages (from-to)530-549
    Number of pages19
    JournalNeuropharmacology
    Volume43
    DOIs
    Publication statusPublished - 2002

    Keywords

    • Thy-1.2 gene promoter
    • transgenic mice
    • extrasynaptic receptor
    • tonic inhibition
    • cerebral cortex
    • cerebellum
    • CEREBELLAR GRANULE CELLS
    • AMINOBUTYRIC ACID(A) RECEPTORS
    • ADULT-RAT BRAIN
    • A RECEPTOR
    • DELTA-SUBUNIT
    • IMMUNOCYTOCHEMICAL DISTRIBUTION
    • PHARMACOLOGICAL PROPERTIES
    • DEVELOPMENTAL-CHANGES
    • EXCITATORY SYNAPSES
    • SYNAPTIC CURRENTS

    Cite this

    Ectopic expression of the GABAA receptor a6 subunit in hippocampal pyramidal neurons produces extrasynaptic receptors and an increased tonic inhibition. / Wisden, William; Cope, D.; Klausberger, T.; Hauer, B.; Sinkkonen, S. T.; Tretter, V.; Lujan, R.; Jones, A.; Korpi, E. R.; Mody, I.; Sieghart, W.; Somogyi, P.

    In: Neuropharmacology, Vol. 43, 2002, p. 530-549.

    Research output: Contribution to journalArticle

    Wisden, W, Cope, D, Klausberger, T, Hauer, B, Sinkkonen, ST, Tretter, V, Lujan, R, Jones, A, Korpi, ER, Mody, I, Sieghart, W & Somogyi, P 2002, 'Ectopic expression of the GABAA receptor a6 subunit in hippocampal pyramidal neurons produces extrasynaptic receptors and an increased tonic inhibition.', Neuropharmacology, vol. 43, pp. 530-549. https://doi.org/10.1016/S0028-3908(02)00151-X
    Wisden, William ; Cope, D. ; Klausberger, T. ; Hauer, B. ; Sinkkonen, S. T. ; Tretter, V. ; Lujan, R. ; Jones, A. ; Korpi, E. R. ; Mody, I. ; Sieghart, W. ; Somogyi, P. / Ectopic expression of the GABAA receptor a6 subunit in hippocampal pyramidal neurons produces extrasynaptic receptors and an increased tonic inhibition. In: Neuropharmacology. 2002 ; Vol. 43. pp. 530-549.
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    abstract = "We generated transgenic (Thy1alpha6) mice in which the GABA(A) receptor alpha6 subunit, whose expression is usually confined to granule cells of cerebellum and cochlear nuclei, is ectopically expressed under the control of the pan-neuronal Thy-1.2 promoter. Strong Thy1alpha6 subunit expression occurs, for example, in deep cerebellar nuclei, layer V iscocortical and hippocampal pyramidal cells and dentate granule cells. Ligand binding and protein biochemistry show that most forebrain alpha6 subunits assemble as alpha6betagamma2-type receptors, and some as alpha1alpha6betagamma2 and alpha3alpha6betagamma2 receptors. Electron microscopic immunogold labeling shows that most Thy1-derived alpha6 immunoreactivity is in the extrasynaptic plasma membrane of dendrites and spines in both layer V isocortical and CA1pyramidal cells. Synaptic immunolabeling is rare. Consistent with the alpha6 subunits' extrasynaptic localization, Thy1alpha6 CA1 pyramidal neurons have a five-fold increased tonic GABA(A) receptor-mediated current compared with wild-type cells; however, the spontaneous IPSC frequency and the mIPSC amplitude in Thy1alpha6 mice decrease 37 and 30{\%}, respectively compared with wild-type, Our results strengthen the idea that GABA(A) receptors containing alpha6 subunits can function as extrasynaptic receptors responsible for tonic inhibition and further suggest that a homeostatic mechanism might operate, whereby increased tonic inhibition causes a compensatory decrease in synaptic GABA(A) receptor responses. (C) 2002 Elsevier Science Ltd. All rights reserved.",
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    author = "William Wisden and D. Cope and T. Klausberger and B. Hauer and Sinkkonen, {S. T.} and V. Tretter and R. Lujan and A. Jones and Korpi, {E. R.} and I. Mody and W. Sieghart and P. Somogyi",
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    TY - JOUR

    T1 - Ectopic expression of the GABAA receptor a6 subunit in hippocampal pyramidal neurons produces extrasynaptic receptors and an increased tonic inhibition.

    AU - Wisden, William

    AU - Cope, D.

    AU - Klausberger, T.

    AU - Hauer, B.

    AU - Sinkkonen, S. T.

    AU - Tretter, V.

    AU - Lujan, R.

    AU - Jones, A.

    AU - Korpi, E. R.

    AU - Mody, I.

    AU - Sieghart, W.

    AU - Somogyi, P.

    PY - 2002

    Y1 - 2002

    N2 - We generated transgenic (Thy1alpha6) mice in which the GABA(A) receptor alpha6 subunit, whose expression is usually confined to granule cells of cerebellum and cochlear nuclei, is ectopically expressed under the control of the pan-neuronal Thy-1.2 promoter. Strong Thy1alpha6 subunit expression occurs, for example, in deep cerebellar nuclei, layer V iscocortical and hippocampal pyramidal cells and dentate granule cells. Ligand binding and protein biochemistry show that most forebrain alpha6 subunits assemble as alpha6betagamma2-type receptors, and some as alpha1alpha6betagamma2 and alpha3alpha6betagamma2 receptors. Electron microscopic immunogold labeling shows that most Thy1-derived alpha6 immunoreactivity is in the extrasynaptic plasma membrane of dendrites and spines in both layer V isocortical and CA1pyramidal cells. Synaptic immunolabeling is rare. Consistent with the alpha6 subunits' extrasynaptic localization, Thy1alpha6 CA1 pyramidal neurons have a five-fold increased tonic GABA(A) receptor-mediated current compared with wild-type cells; however, the spontaneous IPSC frequency and the mIPSC amplitude in Thy1alpha6 mice decrease 37 and 30%, respectively compared with wild-type, Our results strengthen the idea that GABA(A) receptors containing alpha6 subunits can function as extrasynaptic receptors responsible for tonic inhibition and further suggest that a homeostatic mechanism might operate, whereby increased tonic inhibition causes a compensatory decrease in synaptic GABA(A) receptor responses. (C) 2002 Elsevier Science Ltd. All rights reserved.

    AB - We generated transgenic (Thy1alpha6) mice in which the GABA(A) receptor alpha6 subunit, whose expression is usually confined to granule cells of cerebellum and cochlear nuclei, is ectopically expressed under the control of the pan-neuronal Thy-1.2 promoter. Strong Thy1alpha6 subunit expression occurs, for example, in deep cerebellar nuclei, layer V iscocortical and hippocampal pyramidal cells and dentate granule cells. Ligand binding and protein biochemistry show that most forebrain alpha6 subunits assemble as alpha6betagamma2-type receptors, and some as alpha1alpha6betagamma2 and alpha3alpha6betagamma2 receptors. Electron microscopic immunogold labeling shows that most Thy1-derived alpha6 immunoreactivity is in the extrasynaptic plasma membrane of dendrites and spines in both layer V isocortical and CA1pyramidal cells. Synaptic immunolabeling is rare. Consistent with the alpha6 subunits' extrasynaptic localization, Thy1alpha6 CA1 pyramidal neurons have a five-fold increased tonic GABA(A) receptor-mediated current compared with wild-type cells; however, the spontaneous IPSC frequency and the mIPSC amplitude in Thy1alpha6 mice decrease 37 and 30%, respectively compared with wild-type, Our results strengthen the idea that GABA(A) receptors containing alpha6 subunits can function as extrasynaptic receptors responsible for tonic inhibition and further suggest that a homeostatic mechanism might operate, whereby increased tonic inhibition causes a compensatory decrease in synaptic GABA(A) receptor responses. (C) 2002 Elsevier Science Ltd. All rights reserved.

    KW - Thy-1.2 gene promoter

    KW - transgenic mice

    KW - extrasynaptic receptor

    KW - tonic inhibition

    KW - cerebral cortex

    KW - cerebellum

    KW - CEREBELLAR GRANULE CELLS

    KW - AMINOBUTYRIC ACID(A) RECEPTORS

    KW - ADULT-RAT BRAIN

    KW - A RECEPTOR

    KW - DELTA-SUBUNIT

    KW - IMMUNOCYTOCHEMICAL DISTRIBUTION

    KW - PHARMACOLOGICAL PROPERTIES

    KW - DEVELOPMENTAL-CHANGES

    KW - EXCITATORY SYNAPSES

    KW - SYNAPTIC CURRENTS

    U2 - 10.1016/S0028-3908(02)00151-X

    DO - 10.1016/S0028-3908(02)00151-X

    M3 - Article

    VL - 43

    SP - 530

    EP - 549

    JO - Neuropharmacology

    JF - Neuropharmacology

    SN - 0028-3908

    ER -