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J. Biol. Chem., Vol. 282, Issue 40, 29130-29143, October 5, 2007

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GABA_A 6-Containing Receptors Are Selectively Compromised in Cerebellar Granule Cells of the Ataxic Mouse, Stargazer^*

Helen L. Payne¹², William M. Connelly¹³, Jane H. Ives, Reinhard Lehner^¶||4, Birgit Furtmuller^¶||, Werner Sieghart^¶||, Priyanka Tiwari, John M. Lucocq^**5, George Lees, and Christopher L. Thompson

From the Centre for Integrative Neurosciences, School of Biological and Biomedical Sciences, Science Research Laboratories, Durham University, South Road, Durham DH1 3LE, United Kingdom, the ^¶Centre for Brain Research, Medical University Vienna, Spitalgasse 4, Austria, ^||Section for Biochemical Psychiatry, University Clinic for Psychiatry, A-1090 Vienna, Austria,^**School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom, and the Department of Pharmacology and Toxicology, Otago School of Medical Sciences, University of Otago, P. O. Box 56, Dunedin, New Zealand

Stargazer mice fail to express the 2 isoform of transmembrane -amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) receptor regulatory proteins that has been shown to be absolutely required for the trafficking and synaptic targeting of excitatory AMPA receptors in adult murine cerebellar granule cells. Here we show that 30 ± 6% fewer inhibitory -aminobutyric acid, type A (GABA_A), receptors were expressed in adult stargazer cerebellum compared with controls because of a specific loss of GABA_A receptor expression in the cerebellar granule cell layer. Radioligand binding assays allied to in situ immunogold-EM analysis and furosemide-sensitive tonic current estimates revealed that expression of the extrasynaptic (6x) 6-containing GABA_A receptor were markedly and selectively reduced in stargazer. These observations were compatible with a marked reduction in expression of GABA_A receptor 6, (mature cerebellar granule cell-specific proteins), and 3 subunit expression in stargazer. The subunit composition of the residual 6-containing GABA_A receptors was unaffected by the stargazer mutation. However, we did find evidence of an 4-fold up-regulation of 1 receptors that may compensate for the loss of 6-containing GABA_A receptors. PCR analysis identified a dramatic reduction in the steady-state level of 6 mRNA, compatible with 6 being the primary target of the stargazer mutation-mediated GABA_A receptor abnormalities. We propose that some aspects of assembly, trafficking, targeting, and/or expression of extrasynaptic 6-containing GABA_A receptors in cerebellar granule cells are selectively regulated by AMPA receptor-mediated signaling.

Received for publication, January 4, 2007 , and in revised form, July 13, 2007.

^* This work was supported in part by Grants 0543478 and 066204 (to C. L. T.) from the Wellcome Trust and Merck Sharp and Dohme Ltd. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

³ Supported by an Otago Research Grant and the New Zealand Neurological Foundation.

⁴ Supported by the Austrian Science Fund Grant P17203 [GenBank] .

⁵ Supported by the Wellcome Trust, Research Leave Fellowship 059767/Z99/Z, and Tenovus, Scotland, UK.

This paper is dedicated to the memory of Dr. Christopher L. Thompson, an accomplished neuroscientist, an inspirational colleague, and a valued friend, who died on June 5, 2007.

² To whom correspondence should be addressed: School of Biological and Biomedical Sciences, Durham University, Science Research Laboratories, South Road, Durham, DH1 3LE, UK. Tel.: 44-191-334-1312; Fax: 44-191-334-1201; E-mail: H.L.Payne{at}durham.ac.uk.

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