mGlu₅ Positive Allosteric Modulators Facilitate Long-Term Potentiation via Disinhibition Mediated by mGlu₅-Endocannabinoid Signaling

Abstract

Metabotropic glutamate (mGlu) receptor type 5 (mGlu₅) positive allosteric modulators (PAMs) enhance hippocampal long-term potentiation (LTP) and have cognition-enhancing effects in animal models. These effects were initially thought to be mediated by potentiation of mGlu₅ modulation of <i>N</i>-methyl-d-aspartate receptor (NMDAR) currents. However, a biased mGlu₅ PAM that potentiates Gα_q-dependent mGlu₅ signaling, but not mGlu₅ modulation of NMDAR currents, retains cognition-enhancing effects in animal models, suggesting that potentiation of NMDAR currents is not required for these <i>in vivo</i> effects of mGlu₅ PAMs. However, it is not clear whether the potentiation of NMDAR currents is critical for the ability of mGlu₅ PAMs to enhance hippocampal LTP. We now report the characterization of effects of two structurally distinct mGlu₅ PAMs, VU-29 and VU0092273, on NMDAR currents and hippocampal LTP. As with other mGlu₅ PAMs that do not display observable bias for potentiation of NMDAR currents, VU0092273 enhanced both mGlu₅ modulation of NMDAR currents and induction of LTP at the hippocampal Schaffer collateral (SC)-CA1 synapse. In contrast, VU-29 did not potentiate mGlu₅ modulation of NMDAR currents but induced robust potentiation of hippocampal LTP. Interestingly, both VU-29 and VU0092273 suppressed evoked inhibitory postsynaptic currents (eIPSCs) in CA1 pyramidal cells, and this effect was blocked by the cannabinoid receptor type 1 (CB1) antagonist AM251. Furthermore, AM251 blocked the ability of both mGlu₅ PAMs to enhance LTP. Finally, both PAMs failed to enhance LTP in mice with the restricted genetic deletion of mGlu₅ in CA1 pyramidal cells. Taken together with previous findings, these results suggest that enhancement of LTP by mGlu₅ PAMs does not depend on mGlu₅ modulation of NMDAR currents but is mediated by a previously established mechanism in which mGlu₅ in CA1 pyramidal cells induces endocannabinoid release and CB1-dependent disinhibition.