Hyperactivity and Intact Hippocampus-Dependent Learning in Mice Lacking the M₁Muscarinic Acetylcholine Receptor

Abstract

Members of the muscarinic acetylcholine receptor family are thought to play key roles in the regulation of a large number of important functions of the CNS. However, the precise roles of the individual muscarinic receptor subtypes in modulating these processes are not well understood at present, primarily because of the lack of ligands with sufficient receptor subtype selectivity. To investigate the behavioral significance of the M 1 muscarinic receptor (M 1 R), which is abundantly expressed in the forebrain, we subjected M 1 receptor-deficient mice Ϫ/Ϫ mice showed slight performance deficits in auditory-cued fear conditioning and in an eight-arm radial maze, most likely because of the hyperactivity phenotype displayed by the M 1 R Ϫ/Ϫ mice. Our results indicate that M 1 muscarinic receptors play an important role in the regulation of locomotor activity but appear to be less critical for cognitive processes, as generally assumed.

Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory

“…The finding that conditional DH M 3 but not M 1 knockdown impaired memory formation was consistent with findings in constitutive M 1 and M 3 knockouts (Miyakawa et al 2001;Anagnostaras et al 2003). In the RSC, however, only the M 1 /M 3 antagonist telenzepine, but neither M 1 nor M 3 knockdown, impaired learning, indicating that these receptor subtypes have redundant function in memory formation.…”

“…This redundancy of cortical M 1 and M 3 could be particularly evident when manipulations are relatively long lasting, such as genetic ablation, compared with acute pharmacological interventions. For example, even though systemic administration of the M 1 antagonist dicyclomine impairs contextual fear conditioning (Fornari et al 2000), and similarly, systemic administration of an M 1 potentiator rescues the effect of scopolamine on contextual fear conditioning (Ma et al (Miyakawa et al 2001;Anagnostaras et al 2003). A similar argument may be made for the DH's utilization of these receptors during retrieval.…”

“…Yet, after nearly half a century of research, the exact role of acetylcholine in these processes remains elusive and subject to debate. Whether this neurotransmitter is a key player across phases of memory formation and retrieval, and even whether major components of cholinergic signaling contribute to such cognitive processes at all (Miyakawa et al 2001) are still contentious topics. This may be due to the many complexities of the cholinergic system, including the sources and metabolism of acetylcholine, its diverse receptor subtypes, and the neuroanatomical and cell-type specificity of responses to this neurotransmitter.…”

Phospholipase C-β1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration

“…Furthermore, M1 receptor KO mice display locomotor hyperactivity and reduced freezing under SH conditions. 51 In summary, We propose that the attenuation of phosphoinositide hydrolysis due to the absence of PLC-b1 and feedback mechanisms regulating plasticity of muscarinic receptor expression in the adult neocortex may be responsible for the reduction of pirenzepine binding in standard housed KO animals. Muscarinic signaling has been demonstrated to modulate, and to be modulated by, other signaling systems, including dopaminergic 52 and GABAergic pathways.…”

The deletion of M4 muscarinic receptors increases motor activity in females in the dark phase

“…Compelling evidence suggests an important role of the cholinergic system in the control of locomotor activity (Beeri et al., 1995; Martins‐Silva et al., 2011; Miyakawa, Yamada, Duttaroy, & Wess, 2001; Shapovalova, Kamkina, & Mysovskii, 2005). However, the role of M 4 receptors in the control of locomotor activity remains elusive.…”