Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over-expressing hippocampal extrasynaptic [alpha]6[beta] GABA(A) receptors

Kati Saarelainen, Martin Ranna, Holger Rabe, Saku Sinkkonen, Tommi Möykkynen, Mikko Uusi-Oukari, Anni-Maija Linden, Hartmut Luddens, Esa R Korpi

    Research output: Contribution to journalArticleScientificpeer-review

    Abstract

    "The behavioral and functional significance of the extrasynaptic inhibitory GABA(A) receptors in the brain is still poorly known. We used a transgenic mouse line expressing the GABA(A) receptor alpha 6 subunit gene in the forebrain under the Thy-1.2 promoter (Thy1 alpha 6) mice ectopically expressing alpha 6 subunits especially in the hippocampus to study how extrasynaptically enriched alpha beta(gamma 2)-type receptors alter animal behavior and receptor responses. In these mice extrasynaptic alpha 6 beta receptors make up about 10% of the hippocampal GABA(A) receptors resulting in imbalance between synaptic and extrasynaptic inhibition. The synthetic GABA-site competitive agonist gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; 3 mg/kg) induced remarkable anxiolytic-like response in the light : dark exploration and elevated plus-maze tests in Thy1 alpha 6 mice, while being almost inactive in wild-type mice. The transgenic mice also lost quicker and for longer time their righting reflex after 25 mg/kg gaboxadol than wild-type mice. In hippocampal sections of Thy1 alpha 6 mice, the alpha 6 beta receptors could be visualized autoradiographically by interactions between gaboxadol and GABA via [S-35]TBPS binding to the GABA(A) receptor ionophore. Gaboxadol inhibition of the binding could be partially prevented by GABA. Electrophysiology of recombinant GABA(A) receptors revealed that GABA was a partial agonist at alpha 6 beta 3 and alpha 6 beta 3 delta receptors, but a full agonist at alpha 6 beta 3 gamma 2 receptors when compared with gaboxadol. The results suggest strong behavioral effects via selective pharmacological activation of enriched extrasynaptic alpha beta GABA(A) receptors, and the mouse model represents an example of the functional consequences of altered balance between extrasynaptic and synaptic inhibition."
    Original languageEnglish
    JournalJournal of Neurochemistry
    Volume105
    Issue number2
    Pages (from-to)338-350
    Number of pages13
    ISSN0022-3042
    DOIs
    Publication statusPublished - 2008
    MoE publication typeA1 Journal article-refereed

    Fields of Science

    • 311 Basic medicine

    Cite this

    @article{930e6cc891a7488385daeca22784f561,
    title = "Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over-expressing hippocampal extrasynaptic [alpha]6[beta] GABA(A) receptors",
    abstract = "{"}The behavioral and functional significance of the extrasynaptic inhibitory GABA(A) receptors in the brain is still poorly known. We used a transgenic mouse line expressing the GABA(A) receptor alpha 6 subunit gene in the forebrain under the Thy-1.2 promoter (Thy1 alpha 6) mice ectopically expressing alpha 6 subunits especially in the hippocampus to study how extrasynaptically enriched alpha beta(gamma 2)-type receptors alter animal behavior and receptor responses. In these mice extrasynaptic alpha 6 beta receptors make up about 10{\%} of the hippocampal GABA(A) receptors resulting in imbalance between synaptic and extrasynaptic inhibition. The synthetic GABA-site competitive agonist gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; 3 mg/kg) induced remarkable anxiolytic-like response in the light : dark exploration and elevated plus-maze tests in Thy1 alpha 6 mice, while being almost inactive in wild-type mice. The transgenic mice also lost quicker and for longer time their righting reflex after 25 mg/kg gaboxadol than wild-type mice. In hippocampal sections of Thy1 alpha 6 mice, the alpha 6 beta receptors could be visualized autoradiographically by interactions between gaboxadol and GABA via [S-35]TBPS binding to the GABA(A) receptor ionophore. Gaboxadol inhibition of the binding could be partially prevented by GABA. Electrophysiology of recombinant GABA(A) receptors revealed that GABA was a partial agonist at alpha 6 beta 3 and alpha 6 beta 3 delta receptors, but a full agonist at alpha 6 beta 3 gamma 2 receptors when compared with gaboxadol. The results suggest strong behavioral effects via selective pharmacological activation of enriched extrasynaptic alpha beta GABA(A) receptors, and the mouse model represents an example of the functional consequences of altered balance between extrasynaptic and synaptic inhibition.{"}",
    keywords = "311 Basic medicine",
    author = "Kati Saarelainen and Martin Ranna and Holger Rabe and Saku Sinkkonen and Tommi M{\"o}ykkynen and Mikko Uusi-Oukari and Anni-Maija Linden and Hartmut Luddens and Korpi, {Esa R}",
    year = "2008",
    doi = "10.1111/j.1471-4159.2007.05136.x",
    language = "English",
    volume = "105",
    pages = "338--350",
    journal = "Journal of Neurochemistry",
    issn = "0022-3042",
    publisher = "LIPPINCOTT-RAVEN PUBL",
    number = "2",

    }

    Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over-expressing hippocampal extrasynaptic [alpha]6[beta] GABA(A) receptors. / Saarelainen, Kati; Ranna, Martin; Rabe, Holger; Sinkkonen, Saku; Möykkynen, Tommi; Uusi-Oukari, Mikko; Linden, Anni-Maija; Luddens, Hartmut; Korpi, Esa R.

    In: Journal of Neurochemistry, Vol. 105, No. 2, 2008, p. 338-350.

    Research output: Contribution to journalArticleScientificpeer-review

    TY - JOUR

    T1 - Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over-expressing hippocampal extrasynaptic [alpha]6[beta] GABA(A) receptors

    AU - Saarelainen, Kati

    AU - Ranna, Martin

    AU - Rabe, Holger

    AU - Sinkkonen, Saku

    AU - Möykkynen, Tommi

    AU - Uusi-Oukari, Mikko

    AU - Linden, Anni-Maija

    AU - Luddens, Hartmut

    AU - Korpi, Esa R

    PY - 2008

    Y1 - 2008

    N2 - "The behavioral and functional significance of the extrasynaptic inhibitory GABA(A) receptors in the brain is still poorly known. We used a transgenic mouse line expressing the GABA(A) receptor alpha 6 subunit gene in the forebrain under the Thy-1.2 promoter (Thy1 alpha 6) mice ectopically expressing alpha 6 subunits especially in the hippocampus to study how extrasynaptically enriched alpha beta(gamma 2)-type receptors alter animal behavior and receptor responses. In these mice extrasynaptic alpha 6 beta receptors make up about 10% of the hippocampal GABA(A) receptors resulting in imbalance between synaptic and extrasynaptic inhibition. The synthetic GABA-site competitive agonist gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; 3 mg/kg) induced remarkable anxiolytic-like response in the light : dark exploration and elevated plus-maze tests in Thy1 alpha 6 mice, while being almost inactive in wild-type mice. The transgenic mice also lost quicker and for longer time their righting reflex after 25 mg/kg gaboxadol than wild-type mice. In hippocampal sections of Thy1 alpha 6 mice, the alpha 6 beta receptors could be visualized autoradiographically by interactions between gaboxadol and GABA via [S-35]TBPS binding to the GABA(A) receptor ionophore. Gaboxadol inhibition of the binding could be partially prevented by GABA. Electrophysiology of recombinant GABA(A) receptors revealed that GABA was a partial agonist at alpha 6 beta 3 and alpha 6 beta 3 delta receptors, but a full agonist at alpha 6 beta 3 gamma 2 receptors when compared with gaboxadol. The results suggest strong behavioral effects via selective pharmacological activation of enriched extrasynaptic alpha beta GABA(A) receptors, and the mouse model represents an example of the functional consequences of altered balance between extrasynaptic and synaptic inhibition."

    AB - "The behavioral and functional significance of the extrasynaptic inhibitory GABA(A) receptors in the brain is still poorly known. We used a transgenic mouse line expressing the GABA(A) receptor alpha 6 subunit gene in the forebrain under the Thy-1.2 promoter (Thy1 alpha 6) mice ectopically expressing alpha 6 subunits especially in the hippocampus to study how extrasynaptically enriched alpha beta(gamma 2)-type receptors alter animal behavior and receptor responses. In these mice extrasynaptic alpha 6 beta receptors make up about 10% of the hippocampal GABA(A) receptors resulting in imbalance between synaptic and extrasynaptic inhibition. The synthetic GABA-site competitive agonist gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; 3 mg/kg) induced remarkable anxiolytic-like response in the light : dark exploration and elevated plus-maze tests in Thy1 alpha 6 mice, while being almost inactive in wild-type mice. The transgenic mice also lost quicker and for longer time their righting reflex after 25 mg/kg gaboxadol than wild-type mice. In hippocampal sections of Thy1 alpha 6 mice, the alpha 6 beta receptors could be visualized autoradiographically by interactions between gaboxadol and GABA via [S-35]TBPS binding to the GABA(A) receptor ionophore. Gaboxadol inhibition of the binding could be partially prevented by GABA. Electrophysiology of recombinant GABA(A) receptors revealed that GABA was a partial agonist at alpha 6 beta 3 and alpha 6 beta 3 delta receptors, but a full agonist at alpha 6 beta 3 gamma 2 receptors when compared with gaboxadol. The results suggest strong behavioral effects via selective pharmacological activation of enriched extrasynaptic alpha beta GABA(A) receptors, and the mouse model represents an example of the functional consequences of altered balance between extrasynaptic and synaptic inhibition."

    KW - 311 Basic medicine

    U2 - 10.1111/j.1471-4159.2007.05136.x

    DO - 10.1111/j.1471-4159.2007.05136.x

    M3 - Article

    VL - 105

    SP - 338

    EP - 350

    JO - Journal of Neurochemistry

    JF - Journal of Neurochemistry

    SN - 0022-3042

    IS - 2

    ER -