Metabotropic Glutamate Receptor Regulation of Synaptic Transmission at the Schaffer Collateral – CA1 Synapse of the Rat Hippocampus

Recent studies suggest that selective activators of specific subtypes of metabotropic glutamate receptors (mGluRs) have therapeutic potential for a variety of neurological disorders. Eight subtypes of mGluRs have been identified and divided into three groups based on sequence similarity, signal transduction pathways and pharmacological profiles. Different mGluRs are expressed in each subsector of the hippocampus where they have been shown to play important roles in modulating neurotransmission. At the Schaffer collateral-CA1 (SC-CA1) synapse, activation of both group I and group III mGluRs affect synaptic transmission.

Although previous studies indicate that group III mGluRs are involved in modulating synaptic transmission at this synapse, it has been difficult to determine the relative contribution of each receptor subtype due to lack of subtype-selective tools. In addition, previous data suggested that there is a developmental regulation of transmission at this synapse by a group III mGluR. We took advantage of novel subtype-selective pharmacological tools to test this hypothesis. Our data suggest that group III mGluRs regulate transmission at the SC-CA1 synapse throughout development, but there is a developmental regulation of the subtypes involved. Both mGluR7 and mGluR8 serve this role in neonates, whereas mGluR7 is involved in regulating transmission at this synapse throughout postnatal development.

Activation of mGluR5 at the SC-CA1 synapse plays an important role in both long term potentiation (LTP) and long term depression (LTD). We determined the effect of selective positive allosteric modulators (PAMs) of mGluR5 on induction of LTP and LTD at the SC-CA1 synapse. mGluR5-selective PAMs significantly enhanced threshold theta burst stimulation-induced LTP, DHPG-induced LTD and LTD induced by delivery of paired-pulse low frequency stimulation while having no effect on LTP induced by suprathreshold TBS or saturated LTP. The finding that potentiation of mGluR5-mediated responses to stimulation of glutamatergic afferents enhances both LTP and LTD supports the hypothesis that activation of mGluR5 by endogenous glutamate contributes to both forms of plasticity. Furthermore, the dependence of both LTP and LTD on specific patterns of synaptic activity remains intact in the presence of mGluR5 PAMs which may provide a novel approach for treatment of impaired cognitive function.