Loss of metabotropic glutamate receptor-dependent long-term depression via downregulation of mGluR5 after status epilepticus.
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 microM; 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)-(+)-alpha-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.
Kirschstein
Timo
T
Department of Epileptology, University of Bonn, D-53105 Bonn, Germany. timo.kirschstein@uni-rostock.de
Bauer
Michel
M
Müller
Lorenz
L
Rüschenschmidt
Christiane
C
Reitze
Margit
M
Becker
Albert J
AJ
Schoch
Susanne
S
Beck
Heinz
H
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004558:Electric Stimulation / Q000379:methods; D006624:Hippocampus / Q000473:pathology; D000072233:Homer Scaffolding Proteins; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000502:physiology* / Q000528:radiation effects; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D009474:Neurons / Q000502:physiology; D010862:Pilocarpine; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000145:classification / Q000502:physiology*; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; D018094:Receptors, Metabotropic Glutamate; D010862:Pilocarpine; D008734:Methoxyhydroxyphenylglycol; C010117:3,4-dihydroxyphenylglycol