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Kainate down-regulates a subset of GABAA receptor subunits expressed in cultured mouse cerebellar granule cells

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Abstract

The effect of kainate, an agonist selective for ionotropic AMPA/kainate type of glutamate receptors, on GABAA receptor subunit expression in cultured mouse cerebellar granule cells was studied using quantitative RT-PCR, ligand binding and electrophysiology. Chronic kainate treatment, without producing excitotoxicity, resulted in preferential, dose- and time-dependent down-regulation of αl, α6 and β2 subunit mRNA expression, the expression of β3, γ2 and δ subunit mRNAs being less affected. The down-regulation was reversed by DNQX, an AMPA/kainate-selective glutamate receptor antagonist. A 14-day kainate treatment resulted in 46% decrease of total [3H]Ro 15-4513 binding to the benzodiazepine sites. Diazepam-insensitive [3H]Ro 15-4513 binding was decreased by 89% in accordance with very low amount of α6 subunit mRNA present. Diazepam-sensitive [3H]Ro 15-4513 binding was decreased only by 40%, contrasting > 90% decrease in α1 subunit mRNA expression. However, this was consistent with lower potentiation of GABA-evoked currents in kainate-treated than control cells by the α1-selective benzodiazepine site ligand zolpidem, suggesting compensatory expression of α5 (and/or α2 or α3) subunits producing diazepam-sensitive but zolpidem-insensitive receptor subtypes. In conclusion, chronic kainate treatment of cerebellar granule cells selectively down-regulates α1, α6 and β2 subunits resulting in altered GABAA receptor pharmacology.

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Authors and Affiliations

  1. Department of Pharmacology and Clinical Pharmacology, University of Turku, Itäinen Pitkäkatu 4, FIN-20520, Turku, Finland

    Ilkka K. Martikainen, Kadri Lauk, Irma E. Holopainen & Mikko Uusi-Oukari PhD

  2. Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland

    Tommi Möykkynen & Esa R. Korpi

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  1. Ilkka K. Martikainen
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  2. Kadri Lauk
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  3. Tommi Möykkynen
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  4. Irma E. Holopainen
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  6. Mikko Uusi-Oukari PhD
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Correspondence to Mikko Uusi-Oukari PhD.

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The first two authors have equally contributed to this study.

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Martikainen, I.K., Lauk, K., Möykkynen, T. et al. Kainate down-regulates a subset of GABAA receptor subunits expressed in cultured mouse cerebellar granule cells. Cerebellum 3, 27–38 (2004). https://doi.org/10.1080/14734220310020876

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