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

Abstract

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.

Metabotropic glutamate receptor 5 (mGlu5)‐positive allosteric modulators differentially induce or potentiate desensitization of mGlu5 signaling in recombinant cells and neurons

“…Previous studies have indicated that VU0409551 is a biased PAM, with different capacity to enhance mGlu 5 activity depending on the measure of receptor activation (Rook et al ; Ghoshal et al . ; Sengmany et al ). Moreover, the changes in the cellular context in different genetic models of schizophrenia influence the ability of VU0409551 to potentiate different mGlu 5 signaling pathways linked to neuroplasticity (Balu et al .…”

Cholinergic modulation inhibits cortical spreading depression in mouse neocortex through activation of muscarinic receptors and decreased excitatory/inhibitory drive

“…In the CA1 area of rat hippocampal slices, stimulation of cholinergic receptors with carbachol or the M1 preferential agonist 77-LH-28-1 induced LTD (muscarinic LTD or mLTD), which was prevented by the muscarinic antagonist pirenzepine, was NMDA receptordependent, and was linked to NMDA receptors internalization (Jo et al, 2010). Activation of M1 muscarinic receptors induce mLTD also in the prefrontal cortex, where it could depend on the co-activation of mGLuR5 glutamate receptors, and also lead to increased GABAergic transmission on pyramidal neurons (Ghoshal et al, 2017). LTD of glutamatergic synaptic transmission, which often leads to reduction of functional NMDA receptors, could be involved in CSD inhibition.…”

Chronic Adolescent CDPPB Treatment Alters Short-Term, but not Long-Term, Glutamatergic Receptor Expression

“…For example, mGluR5 activation was shown to exert an effect on the GABAergic and dopaminergic systems, which are important for cognitive function [34,35]. A recently developed mGluR5 PAM, VU049551, was shown to have cognitive enhancing effects independent of NMDA receptor activity; VU049551 demonstrated synaptic plasticity effects via the M1 muscarinic acetylcholine receptor [36], highlighting the role mGluR5 PAMs could play on other neurotransmitter systems, beyond glutamatergic receptors.…”