Role of mGlu5 Receptors and Inhibitory Neurotransmission in M1 Dependent Muscarinic LTD in the Prefrontal Cortex: Implications in Schizophrenia.

Selective potentiation of the mGlu5 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 mGlu5-induced modulation of NMDA receptor (NMDAR) currents and NMDAR-dependent synaptic plasticity. However, "biased" mGlu5 PAMs that do not potentiate mGlu5 effects on NMDAR currents show efficacy that is similar to that of prototypical mGlu5 PAMs, suggesting that NMDAR-independent mechanisms must be involved in these actions. We now report that synaptic activation of mGlu5 is required for a form of long-term depression (mLTD) in mouse prefrontal cortex (PFC) that is induced by activation of M1 muscarinic acetylcholine (mAChR) receptors, which was previously thought to be independent of mGlu5 activation. Interestingly, a biased mGlu5 PAM, VU0409551, that does not potentiate mGlu5 modulation of NMDAR currents, potentiated induction of mLTD. Furthermore, coactivation of mGlu5 and M1 receptors increased GABAA-dependent inhibitory tone in the PFC pyramidal neurons, which likely contributes to the observed mLTD. Finally, systemic administration of the biased mGlu5 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 M1 muscarinic receptor PAMs. These studies provide exciting new insights into a novel mechanism by which mGlu5 PAMs can reverse deficits in PFC function and cognition that is independent of modulation of NMDAR currents.