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

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.