Differential activity of mGlu allosteric modulators provides evidence for mGlu heterodimers at hippocampal Schaffer collateral-CA1 synapses.

Glutamate acts at eight metabotropic glutamate (mGlu) receptor subtypes expressed in a partially overlapping fashion in distinct brain circuits. Recent evidence indicates that specific mGlu receptor protomers can heterodimerize and that these heterodimers can exhibit different pharmacology when compared to their homodimeric counterparts. Group III mGlu agonist-induced suppression of evoked excitatory potentials and induction of long-term potentiation at Schaffer collateral-CA1 (SC-CA1) synapses in the rodent hippocampus can be blocked by the selective mGlu negative allosteric modulator (NAM), ADX71743. Curiously, a different mGlu NAM, 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5-c]pyridin-4(5H)-one, failed to block these responses in brain slices despite its robust activity at mGlu homodimers in vitro. We hypothesized that this might result from heterodimerization of mGlu with another mGlu receptor protomer and focused on mGlu as a candidate given the reported effects of mGlu-targeted compounds in the hippocampus. Here, we used complemented donor acceptor-resonance energy transfer to study mGlu heterodimer activation in vitro and observed that ADX71743 blocked responses of both mGlu homodimers and mGlu heterodimers, whereas 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5-c]pyridin-4(5H)-one only antagonized responses of mGlu homodimers. Taken together with our electrophysiology observations, these results suggest that a receptor with pharmacology consistent with an mGlu heterodimer modulates the activity of SC-CA1 synapses. Building on this hypothesis, we identified two additional structurally related mGlu NAMs that also differ in their activity at mGlu heterodimers, in a manner consistent with their ability to inhibit synaptic transmission and plasticity at SC-CA1. Thus, we propose that mGlu heterodimers are a key molecular target for modulating the activity of hippocampal SC-CA1 synapses.