Group I metabotropic glutamate receptor activation produces prolonged epileptiform neuronal synchronization and alters evoked population responses in the hippocampus

Abstract

Glutamate activates a class of receptors coupled to G-proteins that initiate second messenger cascades, change ion channel function, cause release of calcium from intracellular stores, and produce long-term changes in synaptic strength. We used the CA3 region of the adult rat hippocampal slice to evaluate group I metabotropic glutamate receptor (mGluR) activation on epileptiform activity and the population response recorded extracellularly evoked by stratum radiatum stimulation. The selective group I mGluR agonist ( R, S)-3,5-dihydroxyphenylglycine (DHPG) accelerated the rate of bicuculline-induced interictal discharges at concentrations of 10 and 30 μM. At a concentration of 100 μM, DHPG produced prolonged recurrent discharges that last more than 2 s and consisted of an oscillation of the field potential at 2–20 Hz that resembled electrographic seizure activity (ictal). DHPG (100 μM) when bath-applied alone for 30–120 min produced both ictal and interictal discharges that persisted following removal of DHPG from the bathing solution. DHPG (100 μM) reduced the amplitude of the first population spike evoked by stratum radiatum stimulation and changed the relationship of paired evoked population spikes from suppression of the second response relative to the first to facilitation of the second response at interpulse intervals of 15 and 25 ms. To test the possibility that a reduction of the first evoked population spike and loss of inhibition of a second evoked population spike generated prolonged ictal discharges, we used 4-aminopyridine (4-AP 50 μM) to enhance synaptic transmission. 4-AP converted ictal discharges produced by DHPG to an interictal pattern of synchronous activity, reversed the DHPG-induced reduction in the first evoked population spike, and changed paired-pulse facilitation to inhibition. Reversing the changes of evoked population neuronal activity produced by group I mGluR activation favored interictal patterns of epileptiform activity. These results confirm that group I mGluR activation promotes epileptiform activity in the hippocampus and support the hypothesis that a lower efficacy of synaptic transmission favors the generation of prolonged synchronization of neurons that underlies seizures.