Biased M 1 receptor-positive allosteric modulators reveal role of phospholipase D in M 1 -dependent rodent cortical plasticity.

Highly selective, positive allosteric modulators (PAMs) of the M-1 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 M-1 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 M-1 receptor signaling in native systems, and it is not clear whether biased M-1 PAMs display differences in modulating M-1-mediated responses in native tissue. Using PLD inhibitors and PLD knockout mice, we showed that PLD was necessary for the induction of M-1-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Furthermore, biased M-1 PAMs that did not couple to PLD not only failed to potentiate orthosteric agonist-induced LTD but also blocked M-1-dependent LTD in the PFC. In contrast, biased and nonbiased M-1 PAMs acted similarly in potentiating M-1-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 M-1 PAMs function differently in brain regions implicated in cognition.