Modulation of calcium channels by group I and group II metabotropic glutamate receptors in dentate gyrus neurons from patients with temporal lobe epilepsy

Purpose: Metabotropic glutamate receptors (mGluRs) might be promising new d rug targets for the treatment of epilepsy because the expression of certain mGluRs is regulated in epilepsy and because activation of mGluRs results i n distinctive anti- and proconvulsant effects. Therefore, we examined how m GluR activation modulates high-voltage-activated (HVA) Ca2+ channels. Methods: Whole-cell patch-clamp recordings were obtained from granule cells and interneuron-like cells acutely isolated from the dentate gyrus of pati ents with pharmacoresistent temporal lobe epilepsy. Results: Agonists selective for either group I or group II mGluRs rapidly a nd reversibly reduced HVA currents in most dentate gyms cells. These modula tory effects were inhibited by the respective group I and group II mGluR an tagonists. The specific Ca2+ channel antagonists nifedipine and omega-conot oxin GVIA potently occluded the effects of group I and II mGluR agonists, r espectively, indicating that group I mGluRs acted on L-type channels and gr oup II mGluRs affected N-type channels. About two thirds of the responsive neurons were sensitive either to group I or group Il mGluRs, whereas a mino rity of cells showed effects to agonists of both groups, indicating a varia ble mGluR expression pattern. Conclusions: Group I and group II mGluRs are expressed in human dentate gyr us neurons and modulate L- and N-type HVA channels, respectively. The data shed light on the possible cellular sequelae of the mGluR1 upregulation obs erved in human epileptic dentate gyms as well as on possible mGluR-mediated anticonvulsant mechanisms.