Abstracts

Group III metabotropic glutamate receptors are selectively activated by L-AP4, which in the CNS has been shown to inhibit neurotransmitter release. Studies suggest that L-AP4 produces this effect through activation of presynaptic autoreceptors. The high potency of both glutamate and L-AP4 at mGluR4 receptors suggests that these receptors may regulate neuronal excitability. Receptor pharmacology combined with a protein expression pattern which includes entorhinal cortex, the hilar region of the dentate gyrus and the primary terminal fields of the associational fiber-commissural pathway suggest that presynaptic mGluR4 receptors might influence seizure thresholds through modulation of glutamate release. The present study was designed to compare electrically- and chemically induced seizure thresholds in mGluR4 knockout (-/-; KO) and wild type (+/+; WT) mice. Seizure thresholds were determined for mGluR4 WT and KO mice.
Electrically induced seizures: The median convulsant currents (CC50[rsquo]s) were determined for minimal (clonic), maximal (tonic-clonic), and limbic seizures, which were induced via transcorneal stimulation (60 Hz, 0.2 s and 6 Hz, 3 s, respectively).
Kindling: A bipolar electrode was stereotaxically placed into the right amygdala. Following a one-week recovery period, WT and KO animals were stimulated once daily at their individual afterdischarge thresholds (20 stimulations). Behavioral scores and afterdischarge durations were recorded throughout.
Chemically induced seizures: Pentylenetetrazol (0.5%) was infused into the lateral tail vein at a constant rate. Time in seconds was recorded from the infusion start to the appearance of the first twitch and clonic activity. Time was subsequently converted to mg/kg PTZ. Kainic acid (20 mg/kg) or pilocarpine (100 mg/kg) was injected intraperitoneally (i.p.) every 20 min until limbic seizures were observed. Minimal and maximal seizure thresholds did not differ significantly between WT and KO mice (minimal CC50: 7.4 vs 6.6 mA; maximal CC50: 15.1 vs 13.4 mA, WT and KO, respectively). Limbic seizure thresholds were lower in KO mice when compared to WT animals (CC50: 22.5 vs 19.2 mA, WT and KO, respectively). No significant difference was observed in kindling rate or in afterdischarge thresholds. Similarly, no significant difference was observed in PTZ thresholds or in the number of doses of kainic acid or pilocarpine required to produce limbic seizures. Although limbic seizure thresholds were lower in mGluR4 KO mice, the magnitude of the difference was small. No difference between WT and KO animals was observed however in minimal, maximal, kindling, or chemical seizure thresholds, suggesting that mGluR4 receptors are, at best, minimally involved in seizure thresholds. (Supported by Eli Lilly and Company.)