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Down-regulation of mGluR8 in pilocarpine epileptic rats.
- Source :
-
Synapse (New York, N.Y.) [Synapse] 2003 Mar 15; Vol. 47 (4), pp. 278-84. - Publication Year :
- 2003
-
Abstract
- Activation of presynaptic metabotropic glutamate receptors (mGluRs) leads to a powerful inhibition of glutamate release from many synaptic terminals throughout the CNS. mGluRs as autoreceptors are believed to provide a negative feedback system that prevents potentially toxic accumulation of glutamate in the extracellular space during synchronous synaptic activity such as epileptic seizures. In this study we analyzed the function of presynaptic mGluR8 on terminals of the lateral perforant pathway in the pilocarpine model of limbic epilepsy. Field excitatory postsynaptic potentials (fEPSPs) recorded in hippocampal slices of rats that developed spontaneous recurrent seizures after pilocarpine-induced status epilepticus (SRS group) showed a significantly reduced sensitivity to Group III mGluR agonists and severe mossy fiber sprouting. The Group III mGluR agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4, 10 microM) depressed fEPSPs in the SRS group only by 26 +/- 21% compared to 50 +/- 18% in untreated rats. Similarly, the mGluR8 preferring agonist (R,S)-4-phosphonophenylglycine (PPG, 5 microM) was significantly less effective in slices from SRS rats (43 +/- 4% vs. 83 +/- 5%). Concentration-response curves for L-AP4 revealed that the EC(50) values were not different between the control and SRS group (13 +/- 7 microM vs. 9 +/- 9 microM), while the maximal depressing effect was significantly reduced. The remaining depressing effect of L-AP4 in the SRS group could be blocked by the Group III specific antagonists (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG) and alpha-methyl-L-AP4 (MAP4). Rats that did not develop SRS following pilocarpine-induced status epilepticus were indistinguishable from control rats: fEPSPs were highly sensitive to L-AP4 and there was no mossy fiber sprouting. The results show that pilocarpine-induced status epilepticus can lead to a downregulation of mGluR8 and suggest that the condition of SRS is associated with a deteriorated autoregulation of glutamate release.<br /> (Copyright 2003 Wiley-Liss, Inc.)
- Subjects :
- Animals
Down-Regulation
Excitatory Amino Acid Agonists pharmacology
Excitatory Amino Acid Antagonists pharmacology
Glutamic Acid drug effects
Hippocampus drug effects
Hippocampus metabolism
Hippocampus pathology
Immunohistochemistry
Male
Muscarinic Agonists pharmacology
Organ Culture Techniques
Perforant Pathway drug effects
Pilocarpine pharmacology
Rats
Rats, Wistar
Status Epilepticus chemically induced
Synapses drug effects
Synapses metabolism
Excitatory Postsynaptic Potentials drug effects
Glutamic Acid metabolism
Perforant Pathway metabolism
Receptors, Metabotropic Glutamate drug effects
Receptors, Metabotropic Glutamate metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0887-4476
- Volume :
- 47
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Synapse (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 12539201
- Full Text :
- https://doi.org/10.1002/syn.10178