Epilepsia, 48(4):783–792, 2007 Blackwell Publishing, Inc. C  2007 International League Against Epilepsy Anticonvulsive Effect of a Selective mGluR8 Agonist (S)-3,4-Dicarboxyphenylglycine (S-3,4-DCPG) in the Mouse Pilocarpine Model of Status Epilepticus ∗ Feng Li Jiang, ∗ Yong Cheng Tang, ∗ Shwn Chin Chia, ‡Therese M. Jay, and ∗ †Feng Ru Tang ∗ Epilepsy Research Lab, National Neuroscience Institute, and †Department of Anatomy, National University of Singapore, Singapore; and ‡INSERM, U796, Pathophysiology of Psychiatric Disorders, University Paris Descartes, Faculty of Medicine Paris Descartes, Sainte-Anne Hospital, Paris, France Summary: Purpose: We sought to investigate the anticonvul- sive and neuroprotective effect of a selective metabotropic glutamate receptor 8 (mGluR8) agonist (S)-3,4-dicarboxy- phenylglycines (S-3,4-DCPG) on pilocarpine-induced status epilepticus (PISE) and subsequent loss of hilar neurons in the dentate gyrus after systemic (intravenous) or local (intracere- broventricular) administration. We compared the difference in granular cell responses after paired-pulse stimulation of the per- forant pathway and the sensitivity to local injection of S-3,4- DCPG into the stratum granulosum in the control and mice at 2 months after PISE. Methods: We used intravenous, intracerebroventricular, or intrahippocampal administration of S-3,4-DCPG to mice with status epilepticus or temporal lobe epilepsy and neurophysio- logic recording of somatic field excitatory postsynaptic potential (sfEPSP) and population spike (PS) of granular cells in response to perforant-pathway stimulation or S-3,4-DCPG treatment. Results: Intracerebroventricular (1.91 μmol) but not systemic administration of S-3,4-DCPG (at doses of 12.5, 50, 100, 200, 400, 800, and 1,200 mg/kg) could control PISE with no neu- roprotective effect. In epileptic mice, mGluR8-mediated inhi- bition of fEPSPs was reduced significantly in granular cell bodies. Conclusions: At doses ranging from 12.5 to 1,200 mg/kg, intravenous administration of S-3,4-DCPG may not be effective in controlling status epilepticus. Down-regulation of mGluR8 may be related to reduced S-3,4-DCPG–mediated inhibition and the subsequent occurrence of spontaneously recurrent seizures. Key Words: Status epilepticus—Temporal lobe epilepsy—S- 3,4-DCPG. Pre- or postsynaptic localization of metabotropic glu- tamate receptor 8 (mGluR8), one of the group III mGluR subtypes, is observed in the human and rat hippocampus (Shigemoto et al., 1997; Tang et al., 2001a,b; Ferraguti et al., 2005) and neurophysiologic studies have shown that mGluR8 serve as an autoreceptor on lateral perforant path afferents to the dentate gyrus (Dietrich et al., 1997; Zhai et al., 2002). In animal models of seizure, anticon- vulsive effects were found when mGluR8 agonists were administered locally before seizure induction (Tizzano et al., 1995; Suzuki et al., 1996; Tang et al., 1997; Chapman et al., 1999; Gasparini et al., 1999; Moldrich et al., 2001; Barton et al., 2003). However, when den- dritic field excitatory postsynaptic potentials (dfEPSPs) were recorded in the dentate gyrus after lateral perforant- pathway stimulation, a decrease in the mGluR8-mediated Accepted November 14, 2006. Address correspondence and reprint requests to Dr. F.R. Tang at Epilepsy Research Lab, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433. E-mail: Feng Ru Tang@nni.com.sg doi: 10.1111/j.1528-1167.2007.01000.x inhibition was found in the human hippocampus and in the animal model of epilepsy (Dietrich et al., 1999; Friedl et al., 1999; Klapstein et al., 1999; Kral et al., 2003), sug- gesting a deteriorated autoregulation of glutamate release. These data were supported by our immunocytochemical studies showing obvious reduction of mGluR8 labeling in the outer molecular layer of the dentate gyrus (Tang et al., 2001b). In the present study, we aimed to (a) show whether systemic (intravenous) or local (intracerebroventricu- lar) administration of a selective mGluR8 agonist (S)- 3,4-dicarboxyphenylglycine (S-3,4-DCPG) 1h during pilocarpine-induced status epilepticus (PISE) could pro- duce an anticonvulsive effect, (b) compare somatic field excitatory postsynaptic potentials (sfEPSPs) and popu- lation spikes (PSs) in response to paired-pulse stimula- tion of the perforant pathway in control and experimental mice 2 months after PISE, to find whether granule cells were hyperexcitable chronically after PISE or in tem- poral lobe epilepsy (TLE), and to test the sensitivity of granular cell somatic field potentials (sfEPSPs and PSs) 783