Costimulation of AMPA and Metabotropic Glutamate Receptors Underlies Phospholipase C Activation by Glutamate in Hippocampus

Glutamate, a major neurotransmitter in the brain, activates ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs, respectively). The two types of glutamate receptors interact with each other, as exemplified by the modulation of iGluRs by mGluRs. However, the other way of interaction (i.e., modulation of mGluRs by iGluRs) has not received much attention. In this study, we found that group I mGluR-specific agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) alone is not sufficient to activate phospholipase C (PLC) in rat hippocampus, while glutamate robustly activates PLC. These results suggested that additional mechanisms provided by iGluRs are involved in group I mGluR-mediated PLC activation. A series of experiments demonstrated that glutamate-induced PLC activation is mediated by mGluR5 and is facilitated by local Ca²⁺ signals that are induced by AMPA-mediated depolarization and L-type Ca²⁺ channel activation. Finally, we found that PLC and L-type Ca²⁺ channels are involved in hippocampal mGluR-dependent long-term depression (mGluR-LTD) induced by paired-pulse low-frequency stimulation, but not in DHPG-induced chemical LTD. Together, we propose that AMPA receptors initiate Ca²⁺ influx via the L-type Ca²⁺ channels that facilitate mGluR5-PLC signaling cascades, which underlie mGluR-LTD in rat hippocampus.