Elevated levels of group-III metabotropic glutamate receptors in the inferior colliculus of genetically epilepsy-prone rats following intracollicularadministration of L-serine-O-phosphate

The selective group-III metabotropic glutamate receptor agonist, L-serine-O -phosphate (L-SOP), when injected bilaterally into the inferior colliculus of the sound sensitive genetically epilepsy-prone (GEP) rats produces a sho rt proconvulsant excitation followed by a long phase of protection against sound-induced seizures lasting for 2-4 days. We have studied this prolonged suppression of audiogenic seizures using pharmacological and molecular bio logical approaches including semiquantitative RT-PCR and western blotting. The intracerebroventricular injection of the protein synthesis inhibitor cy cloheximide (120 mug) 30 min beforehand significantly reduces the proconvul sant seizure activity and the prolonged anticonvulsant effect of intracolli cular L-SOP (500 nmol/side). The sensitive semiquantitative RT-PCR revealed a significant up-regulation in mGlu(4) and mGlu(7) mRNA levels in the infe rior colliculus at 2 days (maximum suppression of audiogenic seizures) afte r intracollicular L-SOP injection compared with the non-injected, 2-day pos t-vehicle treated and 7-day (return to expressing audiogenic seizures) post -drug or vehicle-treated groups. No significant changes were observed in mG lu(6) or mGlu(8) mRNA expression levels in drug-treated compared with contr ol groups. Examination of mGlu(4a) and mGlu7, protein levels using western blotting showed a significant increase in mGlu(7a) but no significant chang e in mGlu(4a) protein levels 2 days after L-SOP treatment compared with the control groups (non-injected and 2-day vehicle-injected group). These resu lts suggest that up-regulation of mGlu(7) receptors is involved in the prol onged anticonvulsant effect of L-SOP against sound-induced seizures in GEP rats. The potential use of mGlu(7) agonists as novel anti-epileptic agents merits investigation.