Increased Motor-Impairing Effects of the Neuroactive Steroid Pregnanolone in Mice with Targeted Inactivation of the GABA A Receptor γ2 Subunit in the Cerebellum
Endogenous neurosteroids and neuroactive steroids have potent and widespread actions on the brain via inhibitory GABA receptors. In recombinant receptors and genetic mouse models their actions depend on the α, β, and δ subunits of the receptor, especially on those that form extrasynaptic GABA recept...
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Published in | Frontiers in pharmacology Vol. 7; p. 403 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
2016
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Subjects | |
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Abstract | Endogenous neurosteroids and neuroactive steroids have potent and widespread actions on the brain via inhibitory GABA
receptors. In recombinant receptors and genetic mouse models their actions depend on the α, β, and δ subunits of the receptor, especially on those that form extrasynaptic GABA
receptors responsible for non-synaptic (tonic) inhibition, but they also act on synaptically enriched γ2 subunit-containing receptors and even on αβ binary receptors. Here we tested whether behavioral sensitivity to the neuroactive steroid agonist 5β-pregnan-3α-ol-20-one is altered in genetically engineered mouse models that have deficient GABA
receptor-mediated synaptic inhibition in selected neuronal populations. Mouse lines with the GABA
receptor γ2 subunit gene selectively deleted either in parvalbumin-containing cells (including cerebellar Purkinje cells), cerebellar granule cells, or just in cerebellar Purkinje cells were trained on the accelerated rotating rod and then tested for motor impairment after cumulative intraperitoneal dosing of 5β-pregnan-3α-ol-20-one. Motor-impairing effects of 5β-pregnan-3α-ol-20-one were strongly increased in all three mouse models in which γ2 subunit-dependent synaptic GABA
responses in cerebellar neurons were genetically abolished. Furthermore, rescue of postsynaptic GABA
receptors in Purkinje cells normalized the effect of the steroid. Anxiolytic/explorative effects of the steroid in elevated plus maze and light:dark exploration tests in mice with Purkinje cell γ2 subunit inactivation were similar to those in control mice. The results suggest that, when the deletion of γ2 subunit has removed synaptic GABA
receptors from the specific cerebellar neuronal populations, the effects of neuroactive steroids solely on extrasynaptic αβ or αβδ receptors lead to enhanced changes in the cerebellum-generated behavior. |
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AbstractList | Endogenous neurosteroids and neuroactive steroids have potent and widespread actions on the brain via inhibitory GABA
receptors. In recombinant receptors and genetic mouse models their actions depend on the α, β, and δ subunits of the receptor, especially on those that form extrasynaptic GABA
receptors responsible for non-synaptic (tonic) inhibition, but they also act on synaptically enriched γ2 subunit-containing receptors and even on αβ binary receptors. Here we tested whether behavioral sensitivity to the neuroactive steroid agonist 5β-pregnan-3α-ol-20-one is altered in genetically engineered mouse models that have deficient GABA
receptor-mediated synaptic inhibition in selected neuronal populations. Mouse lines with the GABA
receptor γ2 subunit gene selectively deleted either in parvalbumin-containing cells (including cerebellar Purkinje cells), cerebellar granule cells, or just in cerebellar Purkinje cells were trained on the accelerated rotating rod and then tested for motor impairment after cumulative intraperitoneal dosing of 5β-pregnan-3α-ol-20-one. Motor-impairing effects of 5β-pregnan-3α-ol-20-one were strongly increased in all three mouse models in which γ2 subunit-dependent synaptic GABA
responses in cerebellar neurons were genetically abolished. Furthermore, rescue of postsynaptic GABA
receptors in Purkinje cells normalized the effect of the steroid. Anxiolytic/explorative effects of the steroid in elevated plus maze and light:dark exploration tests in mice with Purkinje cell γ2 subunit inactivation were similar to those in control mice. The results suggest that, when the deletion of γ2 subunit has removed synaptic GABA
receptors from the specific cerebellar neuronal populations, the effects of neuroactive steroids solely on extrasynaptic αβ or αβδ receptors lead to enhanced changes in the cerebellum-generated behavior. |
Author | Aller, Maria I Lüddens, Hartmut Luscher, Bernhard Wisden, William Leppä, Elli Vekovischeva, Olga Linden, Anni-Maija Wulff, Peer Korpi, Esa R |
Author_xml | – sequence: 1 givenname: Elli surname: Leppä fullname: Leppä, Elli organization: Department of Pharmacology, Faculty of Medicine, University of Helsinki Helsinki, Finland – sequence: 2 givenname: Anni-Maija surname: Linden fullname: Linden, Anni-Maija organization: Department of Pharmacology, Faculty of Medicine, University of Helsinki Helsinki, Finland – sequence: 3 givenname: Maria I surname: Aller fullname: Aller, Maria I organization: Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández de Elche San Juan de Alicante, Spain – sequence: 4 givenname: Peer surname: Wulff fullname: Wulff, Peer organization: Institute of Physiology, University of Kiel Kiel, Germany – sequence: 5 givenname: Olga surname: Vekovischeva fullname: Vekovischeva, Olga organization: Department of Pharmacology, Faculty of Medicine, University of Helsinki Helsinki, Finland – sequence: 6 givenname: Bernhard surname: Luscher fullname: Luscher, Bernhard organization: Department of Biology, The Pennsylvania State University University Park, PA, USA – sequence: 7 givenname: Hartmut surname: Lüddens fullname: Lüddens, Hartmut organization: Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz Mainz, Germany – sequence: 8 givenname: William surname: Wisden fullname: Wisden, William organization: Department of Life Sciences, Imperial College London London, UK – sequence: 9 givenname: Esa R surname: Korpi fullname: Korpi, Esa R organization: Department of Pharmacology, Faculty of Medicine, University of Helsinki Helsinki, Finland |
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Keywords | extrasynaptic GABAA receptors Purkinje cells neurosteroids motor performance cerebellum |
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Title | Increased Motor-Impairing Effects of the Neuroactive Steroid Pregnanolone in Mice with Targeted Inactivation of the GABA A Receptor γ2 Subunit in the Cerebellum |
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