Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory

Abstract

Understanding how episodic memories are formed and retrieved is necessary if we are to treat disorders in which they malfunction. Muscarinic acetylcholine receptors (mAChR) in the hippocampus and cortex underlie memory formation, but there is conflicting evidence regarding their role in memory retrieval. Additionally, there is no consensus on which mAChR subtypes are critical for memory processing. Using pharmacological and genetic approaches, we found that (1) encoding and retrieval of contextual memory requires mAChR in the dorsal hippocampus (DH) and retrosplenial cortex (RSC), (2) memory formation requires hippocampal M 3 and cooperative activity of RSC M 1 and M 3, and (3) memory retrieval is more impaired by inactivation of multiple M 1 -M 4 mAChR in DH or RSC than inactivation of individual receptor subtypes. Contrary to the view that acetylcholine supports learning but is detrimental to memory retrieval, we found that coactivation of multiple mAChR is required for retrieval of both recently and remotely acquired context memories. Manipulations with higher receptor specificity were generally less potent than manipulations targeting multiple receptor subtypes, suggesting that mAChR act in synergy to regulate memory processes. These findings provide unique insight into the development of therapies for amnestic symptoms, suggesting that broadly acting, rather than receptor-specific, mAchR agonists and positive allosteric modulators may be the most effective therapeutic approach.

The Cholinergic System as a Treatment Target for Opioid Use Disorder

“…This is achieved by increased membrane resistance and input sensitivity, through activation of M 1 , M 3 and M 5 receptors, and reduced neurotransmitter release, through activation of M 2 and M 4 mAChR. These effects are consistent with enhanced specificity of neuronal communication and memory encoding function of mAChRs [107, 108]. …”

Reduced Cholinergic Activity in the Hippocampus of Hippocampal Cholinergic Neurostimulating Peptide Precursor Protein Knockout Mice

“…Acquired context memory may require functions of both M 1 and M 3 muscarinic receptors in the dorsal hippocampus [32]. Alpha 7 nicotinic acetylcholine receptor knockout mice also display no hippocampal-dependent learning phenotype [34]. As a potential reason based on these findings, some combination of dysfunction in cholinergic receptors might be needed to display any behavioral phenotype associated with hippocampal functions and not only an acetylcholine reduction.…”

Mesoscopic Mapping of Stimulus-Selective Response Plasticity in the Visual Pathways Modulated by the Cholinergic System

“…The focus was placed on the most reactive cortical areas, particularly V1, in both hemispheres, contralateral and ipsilateral to the stimulation (cV1 and iV1), as well as five areas of the ventral pathway (AL, A, AM, RL, and PM) that show great tuning for oriented gratings (Smith et al, 2017), and one area of the dorsal pathway (LM). The activity of the retrosplenial cortex (RSC) was assessed because of its role in contextual learning and memory (Makino and Komiyama, 2015;Leaderbrand et al, 2016). High-level areas were also analyzed but not reported as the signal was not significantly (Zhuang et al, 2017) and their belonging to the dorsal (purple) or ventral (blue) stream.…”