Modulation of Long-Term Potentiation and Epileptiform Activity in the Rat Dentate Gyrus by the Group II Metabotropic Glutamate Receptor Subtype mGluR3

摘要

We are the first to report involvement of group II metabotropic glutamate receptors (mGluRs; specifically mGluR3) in modulation of epileptiform activity and long-term potentiation (LTP) in the hippocampal dentate gyrus. By stimulation and/or inhibition of group II mGluRs in rat hippocampal slices, we discovered that: (1) Nacetylaspartylglutamate (NAAG; 50 and 200 M) blocked LTP of extracellular excitatory post-synaptic potentials (EPSPs) after high- frequency stimulation (100Hz; 2s) of the medial perforant path, (2) the beta- isomer of NAAG (beta-NAAG) and ethyl glutamate (100 M; group II mGluR antagonist) prevented this blockade, and (3) beta-NAAG did not affect EPSPs recorded in a paired-pulse paradigm which argues against a presynaptic effect. These data are the first to indicate competitive effects between beta-NAAG and NAAG on mGluR3 receptors. beta-NAAG s effects were characterized using cultured cells. In cerebellar granule cells, we found that: (1) beta-NAAG did not affect inositol phosphate production stimulated by mGluR group I agonists glutamate, L- CCGI, and quisqualate, (2) beta-NAAG reversed decreases in forskolin-stimulated cAMP caused by the mGluR group II agonist DCG-IV, and (3) beta-NAAG did not reverse decreases in forskolin-stimulated cAMP caused by the mGluR group III agonist L-AP4. These results ruled out group I and III mGluRs as effectors of beta-NAAG. We used cells stably transfected with mGluR2 or mGluR3 to determine that beta-NAAG blocked forskolinstimulated cAMP responses to glutamate, NAAG, the nonspecific group I, II agonist trans-ACPD, and the group II agonist DCG-IV via mGluR3, but not mGluR2. We conclude that beta-NAAG is a specific antagonist of mGluR3.