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.

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