Mglu(5) Positive Allosteric Modulators Facilitate Long-Term Potentiation Via Disinhibition Mediated By Mglu(5)-Endocannabinoid Signaling

Metabotropic glutamate (mGlu) receptor type 5 (mGlu(5)) 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 mGlu(5) modulation of N-methyl-D-aspartate receptor (NMDAR) currents. However, a biased mGlu(5) PAM that potentiates G alpha(q)-dependent mGlu(5) signaling, but not mGlu(5) modulation of NMDAR currents, retains cognition-enhancing effects in animal models, suggesting that potentiation of NMDAR currents is not required for these in vivo effects of mGlu(5) PAMs. However, it is not clear whether the potentiation of NMDAR currents is critical for the ability of mGlu(5) PAMs to enhance hippocampal LTP. We now report the characterization of effects of two structurally distinct mGlu(5) PAMs, VU-29 and VU0092273, on NMDAR currents and hippocampal LTP. As with other mGlu(5) PAMs that do not display observable bias for potentiation of NMDAR currents, VU0092273 enhanced both mGlu(5) modulation of NMDAR currents and induction of LTP at the hippocampal Schaffer collateral (SC)-CA1 synapse. In contrast, VU-29 did not potentiate mGlu(5) 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 mGlu(5) PAMs to enhance LTP. Finally, both PAMs failed to enhance LTP in mice with the restricted genetic deletion of mGlu(5) in CA1 pyramidal cells. Taken together with previous findings, these results suggest that enhancement of LTP by mGlu(5) PAMs does not depend on mGlu5 modulation of NMDAR currents but is mediated by a previously established mechanism in which mGlu(5) in CA1 pyramidal cells induces endocannabinoid release and CB1-dependent disinhibition.Y