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The Journal of Neuroscience, July 18, 2007, 27(29):7696-7704; doi:10.1523/JNEUROSCI.4572-06.2007

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Neurobiology of Disease
Loss of Metabotropic Glutamate Receptor-Dependent Long-Term Depression via Downregulation of mGluR5 after Status Epilepticus

Timo Kirschstein,^1,3 * Michel Bauer,^1 * Lorenz Müller,³ Christiane Rüschenschmidt,¹ Margit Reitze,¹ Albert J. Becker,² Susanne Schoch,² and Heinz Beck¹

Departments of ¹Epileptology and ²Neuropathology, University of Bonn, D-53105 Bonn, Germany, and ³Department of Physiology, University of Rostock, D-18057 Rostock, Germany

Correspondence should be addressed to Dr. Timo Kirschstein, Department of Physiology, University of Rostock, Gertrudenstrasse 9, D-18055 Rostock, Germany. Email: timo.kirschstein{at}uni-rostock.de

Synaptic plasticity is thought to be a key mechanism of information storage in the CNS. Different forms of synaptic long-term potentiation have been shown to be impaired in neurological disorders. Here, we show that metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), but not NMDA receptor-dependent LTD at Schaffer collateral–CA1 synapses, is profoundly impaired after status epilepticus. Brief application of the group I mGluR agonist (R,S)-3,5-dihydroxyphenylglycine (100 µM; 5 min) induced mGluR LTD in control, but not in pilocarpine-treated rats. Experiments in the presence of selective inhibitors of either mGluR5 [2-methyl-6-(phenylethynyl)-pyridine] or mGluR1 [7-(hydroxyimino)cyclopropachromen-carboxylate ethyl ester and (S)-(+)--amino-4-carboxy-2-methylbenzeneacetic acid] demonstrate that loss of mGluR LTD is most likely attributable to a loss of mGluR5 function. Quantitative real-time reverse transcription PCR revealed a specific downregulation of mGluR5 mRNA, but not of mGluR1 mRNA in the CA1 region. Furthermore, we detected a strong reduction in mGluR5 protein expression by immunofluorescence and quantitative immunoblotting. Additionally, the scaffolding protein Homer that mediates coupling of mGluR5 to downstream signaling cascades was downregulated. Thus, we conclude that the reduction of mGluR LTD after pilocarpine-induced status epilepticus is the result of the subtype-specific downregulation of mGluR5 and associated downstream signaling components.

Key words: CA1; Schaffer collateral; metabotropic glutamate receptor; DHPG; long-term depression; metaplasticity

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Received Sept. 1, 2005; revised May 31, 2007; accepted May 31, 2007.

Correspondence should be addressed to Dr. Timo Kirschstein, Department of Physiology, University of Rostock, Gertrudenstrasse 9, D-18055 Rostock, Germany. Email: timo.kirschstein{at}uni-rostock.de

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