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

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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