Impaired expression and function of group II metabotropic glutamate receptors in pilocarpine-treated chronically epileptic rats.
Group II metabotropic (mGlu II) receptor subtypes mGlu2 and mGlu3 are important modulators of synaptic plasticity and glutamate release in the brain. Accordingly, several pharmacological ligands have been designed to target these receptors for the treatment of neurological disorders characterized by anomalous glutamate regulation including epilepsy. In this study, we examine whether the expression level and function of mGlu2 and mGlu3 are altered in experimental epilepsy by using immunohistochemistry, Western blot analysis, RT-PCR and extracellular recordings. A down-regulation of mGlu2/3 protein expression at the mossy fiber pathway was associated with a significant reduction in mGlu2/3 protein expression in the hippocampus and cortex of chronically epileptic rats. Moreover, a reduction in mGlu2 and mGlu3 transcripts levels was noticed as early as 24 h after pilocarpine-induced status epilepticus (SE) and persisted during subsequent "latent" and chronic periods. In addition, a significant impairment of mGlu II-mediated depression of field excitatory postsynaptic potentials at mossy fiber-CA3 synapses was detected in chronically epileptic rats. Application of mGlu II agonists (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) induced a significant reduction of the fEPSP amplitude in control rats, but not in chronic epileptic rats. These data indicate a long-lasting impairment of mGlu2/3 expression that may contribute to abnormal presynaptic plasticity, exaggerate glutamate release and hyperexcitability in temporal lobe epilepsy.
Garrido-Sanabria
Emilio R
ER
Department of Biological Sciences, The University of Texas at Brownsville, Texas Southmost College, USA. emilio.garrido@utb.edu
Otalora
Luis F Pacheco
LF
Arshadmansab
Massoud F
MF
Herrera
Berenice
B
Francisco
Sebastian
S
Ermolinsky
Boris S
BS
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002908:Chronic Disease; D003292:Convulsants / Q000633:toxicity; D003521:Cyclopropanes / Q000494:pharmacology; D004827:Epilepsy / Q000139:chemically induced / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007150:Immunohistochemistry; D009473:Neuronal Plasticity / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010862:Pilocarpine / Q000633:toxicity; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000927:Anticonvulsants; D003292:Convulsants; D003521:Cyclopropanes; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D010862:Pilocarpine; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D005998:Glycine