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 N-methyl-d-aspartate receptor (NMDAR) currents. However, a biased mGlu5 PAM that potentiates Gαq-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 in vivo 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.