Activation of Metabotropic Glutamate Receptor 7 Is Required for Induction of Long-Term Potentiation at SC-CA1 Synapses in the Hippocampus

Of the eight metabotropic glutamate (mGlu) receptor subtypes, only mGlu(7) is expressed presynaptically at the Schaffer collateral (SC)-CA1 synapse in the hippocampus in adult animals. Coupled with the inhibitory effects of Group III mGlu receptor agonists on transmission at this synapse, mGlu(7) is thought to be the predominant autoreceptor responsible for regulating glutamate release at SC terminals. However, the lack of mGlu(7)-selective pharmacological tools has hampered direct testing of this hypothesis. We used a novel, selective mGlu(7)-negative allosteric modulator (NAM), ADX71743, and a newly described Group III mGlu receptor agonist, LSP4-2022, to elucidate the role of mGlu(7) in modulating transmission in hippocampal area CA1 in adult C57BL/6J male mice. Interestingly, although mGlu(7) agonists inhibit SC-CA1 EPSPs, we found no evidence for activation of mGlu(7) by stimulation of SC-CA1 afferents. However, LSP4-2022 also reduced evoked monosynaptic IPSCs in CA1 pyramidal cells and, in contrast to its effect on SC-CA1 EPSPs, ADX71743 reversed the ability of high-frequency stimulation of SC afferents to reduce IPSC amplitudes. Furthermore, blockade of mGlu(7) prevented induction of LTP at the SC-CA1 synapse and activation of mGlu(7) potentiated submaximal LTP. Together, these data suggest that mGlu(7) serves as a heteroreceptor at inhibitory synapses in area CA1 and that the predominant effect of activation of mGlu(7) by stimulation of glutamatergic afferents is disinhibition, rather than reduced excitatory transmission. Furthermore, this mGlu(7)-mediated disinhibition is required for induction of LTP at the SC-CA1 synapse, suggesting that mGlu(7) could serve as a novel therapeutic target for treatment of cognitive disorders.