The Journal of Neuroscience, August 16, 2006, 26(33):8600-8608; doi:10.1523/JNEUROSCI.1088-06.2006
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Neurobiology of Disease
Aberrant GABAA Receptor Expression in the Dentate Gyrus of the Epileptic Mutant Mouse Stargazer
Helen L. Payne,1
Peter S. Donoghue,1
William M. K. Connelly,2
Sabine Hinterreiter,3,4
Priyanka Tiwari,1
Jane H. Ives,1
Victoria Hann,1
Werner Sieghart,3,4
George Lees,2 and
Christopher L. Thompson1
1School of Biological and Biomedical Sciences, Science Research Laboratories, Durham University, Durham DH1 3LE, United Kingdom, 2Department of Pharmacology and Toxicology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand, 3Centre for Brain Research, Medical University Vienna, A-1090 Vienna, Austria, and 4Section for Biochemical Psychiatry, University Clinic for Psychiatry, A-1090 Vienna, Austria
Correspondence should be addressed to Dr. Christopher L. Thompson, School of Biological and Biomedical Sciences, Durham University, Science Research Laboratories, South Road, Durham DH1 3LE, UK. Email: c.l.thompson{at}durham.ac.uk
Stargazer (stg) mutant mice fail to express stargazin [transmembrane AMPA receptor regulatory protein 
2 (TARP2)] and consequently experience absence seizure-like thalamocortical spike-wave discharges that pervade the hippocampal formation via the dentate gyrus (DG). As in other seizure models, the dentate granule cells of stg develop elaborate reentrant axon collaterals and transiently overexpress brain-derived neurotrophic factor. We investigated whether GABAergic parameters were affected by the stg mutation in this brain region. GABAA receptor (GABAR) 
4 and 
3 subunits were consistently upregulated, GABAR 
expression appeared to be variably reduced, whereas GABAR 1, 2, and 2 subunits and the GABAR synaptic anchoring protein gephyrin were essentially unaffected. We established that the 42 subunit-containing, flunitrazepam-insensitive subtype of GABARs, not normally a significant GABAR in DG neurons, was strongly upregulated in stg DG, apparently arising at the expense of extrasynaptic 4-containing receptors. This change was associated with a reduction in neurosteroid-sensitive GABAR-mediated tonic current. This switch in GABAR subtypes was not reciprocated in the tottering mouse model of absence epilepsy implicating a unique, intrinsic adaptation of GABAergic networks in stg.
Contrary to previous reports that suggested that TARP2 is expressed in the dentate, we find that TARP2 was neither detected in stg nor control DG. We report that TARP8 is the principal TARP isoform found in the DG and that its expression is compromised by the stargazer mutation. These effects on GABAergic parameters and TARP8 expression are likely to arise as a consequence of failed expression of TARP2 elsewhere in the brain, resulting in hyperexcitable inputs to the dentate.
Key words: hippocampus; stargazin; TARPs; AMPA receptors; GABAA receptors; absence epilepsy
Received Nov. 30, 2005;
revised June 15, 2006;
accepted July 6, 2006.
Correspondence should be addressed to Dr. Christopher L. Thompson, School of Biological and Biomedical Sciences, Durham University, Science Research Laboratories, South Road, Durham DH1 3LE, UK. Email: c.l.thompson{at}durham.ac.uk
