The M3-muscarinic receptor regulates learning and memory in a receptor phosphorylation/arrestin-dependent manner

Poulin, B. et al. (2010) The M3-muscarinic receptor regulates learning and memory in a receptor phosphorylation/arrestin-dependent manner. Proceedings of the National Academy of Sciences of the United States of America, 107(20), pp. 9440-9445. (doi: 10.1073/pnas.0914801107) (PMID:20439723) (PMCID:PMC2889095)

Abstract

Degeneration of the cholinergic system is considered to be the underlying pathology that results in the cognitive deficit in Alzheimer's disease. This pathology is thought to be linked to a loss of signaling through the cholinergic M1-muscarinic receptor subtype. However, recent studies have cast doubt on whether this is the primary receptor mediating cholinergic-hippocampal learning and memory. The current study offers an alternative mechanism involving the M3-muscarinic receptor that is expressed in numerous brain regions including the hippocampus. We demonstrate here that M3-muscarinic receptor knockout mice show a deficit in fear conditioning learning and memory. The mechanism used by the M3-muscarinic receptor in this process involves receptor phosphorylation because a knockin mouse strain expressing a phosphorylation-deficient receptor mutant also shows a deficit in fear conditioning. Consistent with a role for receptor phosphorylation, we demonstrate that the M3-muscarinic receptor is phosphorylated in the hippocampus following agonist treatment and following fear conditioning training. Importantly, the phosphorylation-deficient M3-muscarinic receptor was coupled normally to Gq/11-signaling but was uncoupled from phosphorylation-dependent processes such as receptor internalization and arrestin recruitment. It can, therefore, be concluded that M3-muscarinic receptor–dependent learning and memory depends, at least in part, on receptor phosphorylation/arrestin signaling. This study opens the potential for biased M3-muscarinic receptor ligands that direct phosphorylation/arrestin-dependent (non-G protein) signaling as being beneficial in cognitive disorders.

• Item Type: Articles
• Additional Information: A.B.T. is supported by the Wellcome Trust (047600). R.P. is supported by Marie Curie Excellence Grant MEXT-CT-2006-042265 from the European Commission.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Bourgognon, Dr Julie-Myrtille
• Authors: Poulin, B., Butcher, A., McWilliams, P., Bourgognon, J.-M., Pawlak, R., Kong, K. C., Bottrill, A., Mistry, S., Wess, J., Rosethorne, E. M., Charlton, S. J., and Tobin, A. B.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing
• Journal Name: Proceedings of the National Academy of Sciences of the United States of America
• Publisher: National Academy of Sciences
• ISSN: 0027-8424
• ISSN (Online): 1091-6490