Modulation of excitatory synaptic transmission by metabotropic glutamate receptors in hippocampal microcultures

Glutamate-mediated fast excitatory synaptic transmission is subject to modulation by multiple neurotransmitters and neuropeptides. One such potential modulator is glutamate itself, acting through G protein-coupled metabotropic glutamate receptors (mGluRs). To date, eight subtypes of mGluRs (mGluR1–8) have been cloned from mammalian brain. These subtypes can be divided into three groups (I, II, and III) based on sequence homology, signal transduction mechanism, and agonist pharmacology. Previous work in our laboratory demonstrated that global mGluR agonists modulated excitatory transmission in hippocampal microisland cultures. We examined this modulation in more detail to determine the effects of each mGluR subgroup and assess their mechanism of action.; The group I mGluR agonist, DHPG, potentiated the peak amplitude of excitatory postsynaptic currents (EPSCs). In contrast, the group II mGluR agonist, DCG-IV, or the group III mGluR agonist, AP4, depressed EPSCs dose-dependently. LY341495, an mGluR antagonist with varying potency on group II and III mGluRs, blocked the actions of DCG-IV or AN at appropriate concentrations. In contrast to EPSCs, DCG-IV had no effect on inhibitory postsynaptic currents.; Both DCG-IV and AN decreased paired-pulse depression. DCG-IV also decreased spontaneous, miniature EPSC (mEPSC) frequency but had no effect on mEPSC amplitude. This suggests that group II and III mGluRs inhibit EPSCs presynaptically. Studies examining endogenous activation of mGluRs suggested that synaptically activated mGluRs have, at most, only a very small role in modulating responses to 20 Hz trains.; Immunocytochemical studies demonstrated the presence of multiple mGluRs in our cultures. mGluR1 and mGluR5 were detected in approximately 50% of excitatory and inhibitory neuronal somata. mGluR4 was detected in 80% of GABAergic neurons, but in only 35% of glutamatergic neurons. mGluR2, mGluR3, and mGluR7 had very low expression in neurons. However, mGluR2/3 showed very strong staining in a rare population of cells that share morphological features with immature neurons. In summary, hippocampal cultures express mGluRs from all three groups. Functionally, all three groups modulate excitatory transmission, with group II and III mGluRs acting presynaptically.