Abstracts

Metabotropic glutamate mGluR8 receptors are located on the terminals of the lateral perforant path in the dentate gyrus. Stimulation of mGluR8 receptors is known to decrease the release of glutamate. The lateral perforant path - hippocampal pathway is part of the limbic seizure circuitry, and presynaptic mGluR8 receptors might be involved in dampening or terminating seizure propagation through this pathway by decreasing the release of glutamate onto neurons in the dentate gyrus. The purpose of the present studies was therefore to compare the seizure susceptibility of mGluR8 (-/-; KO) and wild type mGluR8 (+/+;WT) mice. We compared the differences between KO and WT mice in the amygdala-kindling model, as well as thresholds in electrically and chemically induced acute seizure models. In addition, we determined the anticonvulsant effects of carbamazepine and levetiracetam in kindled mice. A bipolar electrode was stereotaxically implanted into the right amygdala of CD-1 WT and KO mice. Mice were given 15 daily stimulations (500 mA, 60 Hz, 1 sec). Behavioral seizure scores (Racine scale) and EEG after-discharge (AD) durations were recorded throughout. Post-kindling seizure thresholds and AD durations were also determined. After thresholds stabilized, the anticonvulsant effects of carbamazepine (30 mg/kg, IP) and levetiracetam (50 mg/kg, IP) were determined. Median convulsant currents (CC50s) were determined for producing electrically-induced clonic and tonic seizures (60 Hz, 0.2 sec) as well as limbic seizures (6 Hz, 3 sec). In chemically induced seizure models, kainate (20 mg/kg, IP) or pilocarpine (100 mg/kg, IP) were injected every 20 minutes until the first limbic seizure. The number of doses and minutes to onset of limbic seizures were recorded. During kindling development, KO mice had higher seizure scores but comparable AD durations compared to WT mice. Post-kindling, seizure thresholds were significantly lower in KO mice. Carbamazepine and levetiracetam increased the seizure thresholds both KO and WT. Electrical seizure thresholds did not significantly differ between KO and WT. In addition, the threshold doses of kainate and pilocarpine required to produce limbic seizures did not differ between KO and WT mice. mGluR8 KO mice kindled more rapidly in the amygdala kindling model. However, seizure thresholds for electrically-induced clonic, tonic and limbic seizures as well as for kainate- and pilocarpine-induced seizures did not differ between KO and WT mice. The present results suggest that mGluR8 receptors may be involved in dampening kindling-induced sensitization of the lateral perforant path - hippocampal pathway, and as such might be a functional part of the dentate gate. (Supported by Eli Lilly and Company)