Research ArticleNeuroscience

Biased M1 receptor–positive allosteric modulators reveal role of phospholipase D in M1-dependent rodent cortical plasticity

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Science Signaling  03 Dec 2019:
Vol. 12, Issue 610, eaax2057
DOI: 10.1126/scisignal.aax2057

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Modulating receptor signaling

The M1 subtype of the muscarinic acetylcholine receptor family of GPCRs is an important therapeutic target in the treatment of schizophrenia and Alzheimer’s disease. Specific positive allosteric modulators (PAMs) of the M1 receptor enhance cognition in animal models of these disorders but have limited efficacy because of other pharmacological properties. Moran et al. used biased M1 receptor PAMs that differentially affected downstream signaling to show that phospholipase D (PLD) was required for M1 receptor–mediated long-term depression in the mouse prefrontal cortex, a process implicated in the therapeutic benefits of targeting this receptor. Together, these data suggest that different PAMs could have distinct abilities to regulate cognitive function or other responses in vivo.


Highly selective, positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach to potentially improve cognitive function in patients suffering from Alzheimer’s disease and schizophrenia. Discovery programs have produced a structurally diverse range of M1 receptor PAMs with distinct pharmacological properties, including different extents of agonist activity and differences in signal bias. This includes biased M1 receptor PAMs that can potentiate coupling of the receptor to activation of phospholipase C (PLC) but not phospholipase D (PLD). However, little is known about the role of PLD in M1 receptor signaling in native systems, and it is not clear whether biased M1 PAMs display differences in modulating M1-mediated responses in native tissue. Using PLD inhibitors and PLD knockout mice, we showed that PLD was necessary for the induction of M1-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Furthermore, biased M1 PAMs that did not couple to PLD not only failed to potentiate orthosteric agonist–induced LTD but also blocked M1-dependent LTD in the PFC. In contrast, biased and nonbiased M1 PAMs acted similarly in potentiating M1-dependent electrophysiological responses that were PLD independent. These findings demonstrate that PLD plays a critical role in the ability of M1 PAMs to modulate certain central nervous system (CNS) functions and that biased M1 PAMs function differently in brain regions implicated in cognition.

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