Elevated levels of group-III metabotropic glutamate receptors in the inferior colliculus of genetically epilepsy-prone rats following intracollicular administration 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 short 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 biological approaches including semiquantitative RT-PCR and western blotting. The intracerebroventricular injection of the protein synthesis inhibitor cycloheximide (120 microg) 30 min beforehand significantly reduces the proconvulsant seizure activity and the prolonged anticonvulsant effect of intracollicular 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 inferior colliculus at 2 days (maximum suppression of audiogenic seizures) after intracollicular L-SOP injection compared with the non-injected, 2-day post-vehicle treated and 7-day (return to expressing audiogenic seizures) post-drug or vehicle-treated groups. No significant changes were observed in mGlu(6) or mGlu(8) mRNA expression levels in drug-treated compared with control groups. Examination of mGlu(4a) and mGlu(7a) protein levels using western blotting showed a significant increase in mGlu(7a) but no significant change 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 results suggest that up-regulation of mGlu(7) receptors is involved in the prolonged 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.
Yip
P K
PK
Department of Neurology, Institute of Psychiatry, King's College London, London, UK.
Meldrum
B S
BS
Rattray
M
M
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology / Q000523:psychology; D005260:Female; D020022:Genetic Predisposition to Disease; D007245:Inferior Colliculi / Q000378:metabolism*; D007267:Injections; D008297:Male; D010768:Phosphoserine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000517:prevention & control; D015854:Up-Regulation
D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7; D010768:Phosphoserine; C108823:metabotropic glutamate receptor 4