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Selective potentiation of the mGlu 5 subtype of metabotropic glutamate (mGlu) receptor using positive allosteric modulators (PAMs) has robust cognition-enhancing effects in rodent models that are relevant for schizophrenia. Until recently, these effects were thought to be due to potentiation of mGlu 5 -induced modulation of NMDA receptor (NMDAR) currents and NMDAR-dependent synaptic plasticity. However, "biased" mGlu 5 PAMs that do not potentiate mGlu 5 effects on NMDAR currents show efficacy that is similar to that of prototypical mGlu 5 PAMs, suggesting that NMDAR-independent mechanisms must be involved in these actions. We now report that synaptic activation of mGlu 5 is required for a form of long-term depression (mLTD) in mouse prefrontal cortex (PFC) that is induced by activation of M 1 muscarinic acetylcholine (mAChR) receptors, which was previously thought to be independent of mGlu 5 activation. Interestingly, a biased mGlu 5 PAM, VU0409551, that does not potentiate mGlu 5 modulation of NMDAR currents, potentiated induction of mLTD. Furthermore, coactivation of mGlu 5 and M 1 receptors increased GABA A -dependent inhibitory tone in the PFC pyramidal neurons, which likely contributes to the observed mLTD. Finally, systemic administration of the biased mGlu 5 PAM reversed deficits in mLTD and associated cognitive deficits in a model of cortical disruption caused by repeated phencyclidine exposure that is relevant for schizophrenia and was previously shown to be responsive to selective M 1 muscarinic receptor PAMs. These studies provide exciting new insights into a novel mechanism by which mGlu 5 PAMs can reverse deficits in PFC function and cognition that is independent of modulation of NMDAR currents.