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

Abstract

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 mg) 30 min beforehand signi®cantly reduces the proconvulsant seizure activity and the prolonged anticonvulsant effect of intracollicular L-SOP (500 nmol/side). The sensitive semiquantitative RT-PCR revealed a signi®cant 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 vehicletreated groups. No signi®cant 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 signi®cant increase in mGlu 7a but no signi®cant change in mGlu 4a protein levels 2 days after L-SOP treatment compared with the control groups (non-injected and 2-day vehicleinjected 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.

Increased Seizure Susceptibility in Mice Lacking Metabotropic Glutamate Receptor 7

“…A recent finding that further strengthens a role for mGluR7 receptors in epilepsy is its selective upregulation in the inferior colliculus of genetically epilepsy-prone (GEP) rats. This was shown to be associated with a prolonged anticonvulsant effect of intracollicular administrated L-SOP against soundinduced seizures in GEP rats (Yip et al, 2001).…”

“…The notion that group III mGluRs are potential targets for novel antiepileptic drugs is supported by results in rodent models of epilepsy in which group III selective agonists showed prolonged anticonvulsant actions [L-AP4, L-SOP (Tizzano et al, 1995;Tang et al, 1997); (R,S)-PPG (Chapman et al, 1999;Gasparini et al, 1999); L-SOP (Yip et al, 2001)] and increased seizure threshold (L-AP4; Suzuki et al, 1999) or seizure latency (Thomsen and Dalby, 1998). In addition, in epilepsy the changes have been noted in the agonist sensitivity (Neugebauer et al, 2000), expression (Aronica et al, 1997;Liu et al, 2000;Yip et al, 2001), and receptor responses of group III mGluRs (Holmes et al, 1996;Neugebauer et al, 1997;Dietrich et al, 1999;Klapstein et al, 1999).…”

“…In addition, in epilepsy the changes have been noted in the agonist sensitivity (Neugebauer et al, 2000), expression (Aronica et al, 1997;Liu et al, 2000;Yip et al, 2001), and receptor responses of group III mGluRs (Holmes et al, 1996;Neugebauer et al, 1997;Dietrich et al, 1999;Klapstein et al, 1999). The lack of specific ligands to address mGluR7 function prompted us to generate mice lacking these receptors.…”

Medial Perforant Path Inhibition Mediated by mGluR7 Is Reduced After Status Epilepticus

“…Alterations in synaptic plasticity can powerfully refine synaptic connectivity and have long been thought to importantly contribute to hyperexcitability and epilepsy (Schwartzkroin 2001). Third, a focal injection of the group III agonist L-SOP into the inferior colliculus produced a short (10 min) proconvulsant excitation in sound-sensitive genetically epilepsy-prone rats, followed by a prolonged phase of enhanced protection from subsequent sound-induced seizures that lasted for 2-4 days (Yip et al 2001). The authors reported an up-regulation in both mRNA and protein levels of mGluR7 in the inferior colliculus that they hypothesized was responsible for the prolonged anticonvulsant effect.…”

“…Second, there is evidence for increased group II mGluR function after PILO that appears to contribute to disinhibition of dentate granule cells (GCs) (Doherty and Dingledine 2001). Third, agonists for group II or III mGluRs can be both anticonvulsive (Attwell et al 1998;Folbergrova et al 2001;Yip et al 2001) and neuroprotective (Allen et al 1999;Gasparini et al 1999). Finally, studies of mGluR knockout (KO) mice indicate that mice lacking mGluR4 are more resistant to absence seizures (Snead et al 2000), whereas mGluR7-null mice develop seizures after ϳ12 wk of age (Sansig et al 2001).…”