Corey R. Hopkins

Of the eight metabotropic glutamate (mGlu) receptor subtypes, only mGlu₇is 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, mGlu₇is thought to be the predominant autoreceptor responsible for regulating glutamate release at SC terminals. However, the lack of mGlu₇-selective pharmacological tools has hampered direct testing of this hypothesis. We used a novel, selective mGlu₇-negative allosteric modulator (NAM), ADX71743, and a newly described Group III mGlu receptor agonist, LSP4-2022, to elucidate the role of mGlu₇in modulating transmission in hippocampal area CA1 in adult C57BL/6J male mice. Interestingly, although mGlu₇agonists inhibit SC-CA1 EPSPs, we found no evidence for activation of mGlu₇by 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 mGlu₇prevented induction of LTP at the SC-CA1 synapse and activation of mGlu₇potentiated submaximal LTP. Together, these data suggest that mGlu₇serves as a heteroreceptor at inhibitory synapses in area CA1 and that the predominant effect of activation of mGlu₇by stimulation of glutamatergic afferents is disinhibition, rather than reduced excitatory transmission. Furthermore, this mGlu₇-mediated disinhibition is required for induction of LTP at the SC-CA1 synapse, suggesting that mGlu₇could serve as a novel therapeutic target for treatment of cognitive disorders.