The role of muscarinic receptors in learning and memory

Kok Choi Kong, Andrew Tobin. University of Leicester, Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, Leicestershire, U.K., LE1 9HN, UK

It has been well established that muscarinic acetylcholine receptors play a vital role in the regulation of cognitive functions. However, the specific roles of individual muscarinic receptor subtypes (M1-M5) in learning and memory still remained poorly understood and ill-defined. Previous studies involving central administration of muscarinic antagonists and lesion experiments have demonstrated that muscarinic receptors located in the hippocampus are of particular importance for the processes of learning and memory (Bartus et al., 1982; Fibiger et al., 1991; Iversen, 1997). Study from our laboratory has also shown that M3-muscarinic receptor-knockout mice exhibit a deficit in fear conditioning learning and memory (Poulin et al., 2010), hence demonstrating a role for M3-muscarinic receptor in learning and memory.

In current study, we examined the role of muscarinic receptors in the regulation of cognitive behaviour further by characterising two other muscarinic receptor- (M1 and M4) knockout mice (M1KO and M4KO). 8 to 10 weeks old, male wild-type C57BL/6 (WT) and the two knockout mice strains were subjected to a variety of behavioural tests including fear conditioning learning and memory, pain threshold, elevated plus maze and burrowing. In agreement with previous study (Ma et al., 2010), M1KO mice show a deficit in the contextual learning and memory compared to the WT (26.32±2.10%, n = 30 for WT vs 15.29±1.56%, n = 20 for M1KO; p<0.001). Interestingly, M4KO mice showed a deficit in both contextual (25.42±2.46%, n = 22 for WT vs 12.81±2.23%, n = 17 for M4KO; p<0.001) and cued-(33.09±2.69%, n = 22 for WT vs 18.58±2.93%, n = 17 for M4KO; p<0.001) learning and memory tests. Moreover, M4KO mice also showed a significant reduction in burrowing (79.60±7.30g, n = 15 for WT vs 46.57±7.73g, n = 14 for M4KO; p<0.01, for 2 hour burrowing), which suggests a defect in the hippocampus or prefrontal cortex functions (Deacon et al., 2002).

In conclusion, the current study demonstrated a novel role of M4-muscarinic receptor in the regulation of both hippocampal- (contextual) and amygdala (cued)-based learning and memory while the M1-muscarinic receptor is involved mainly in the former.

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Iversen, S.D. & Muller R.U. (1997) Curr Opin Neurobiol. 7, 151-156.

Ma, L. et al. (2009) Proc Natl Acad Sci U S A. 106, 15950-15955.

Poulin, B. et al. (2010) Proc Natl Acad Sci U S A. 107, 9440-9445.

This work is funded by the Wellcome Trust (Grant 047600).