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M1 muscarinic receptors have long been identified as a potential therapeutic target for the treatment of cognitive impairment in Alzheimer's disease (AD). Our previous study has shown that M1 receptors promote membrane insertion and synaptic delivery of AMPA receptor GluA1 subunit. In this study, we sought to determine whether activation of M1 receptor would rescue the cognitive impairment in AD model mice through modulation of GluA1 subunit. For the mice injected with aggregated β-amyloid (Aβ) fragments to impair learning and memory, activation of M1 receptors could rescue it by reducing the latency to find the platform and spending more time in the target quadrant in the probe test in the Morris water maze. However, such an effect was ablated in mice with Ser845 residue of GluA1 mutated to alanine. Furthermore, the activation of M1 receptors enhanced the expression of GluA1 and its phosphorylation at Ser845 and drove GluA1 to incorporate with PSD95, a postsynaptic marker, in the hippocampi from Aβ-injected wild type mice but not from the mutant mice. Moreover, for 9-month-old APP/PS1 transgenic AD model mice, which may resemble the late AD, M1 receptor activation could not improve the cognitive impairment significantly. In addition, the enhancement of GluA1 expression and its phosphorylation at Ser845 were not observed in their hippocampi. Taken together, the study indicated that M1 receptor activation rescued the cognitive deficit through modulating the trafficking of GluA1-containing AMPA receptors and the therapeutics targeting M1 receptors should aim at mild AD or even pre-AD. • M1 receptor activation rescues Aβ-induced cognitive impairment in wild type mice but not in GluA1 S845A mutant mice. • Chronic activation of M1 receptors enhances the expression of GluA1 through its phosphorylation at Ser845. • M1 receptor activation does not significantly improve learning and memory in 9-month APP/PS1 mice. • The potential therapeutics targeting M1 receptors may be appropriate for early AD or even pre-AD. [ABSTRACT FROM AUTHOR]

Abstract Cognitive flexibility is an important aspect of executive function. The cholinergic system, an important component of cognition, has been shown to modulate cognitive flexibility mainly through the striatum and prefrontal cortex. The role of M1 muscarinic receptors (M1 mAChRs), an important therapeutic target in the cholinergic system, in hippocampus-dependent cognitive flexibility is unclarified. In the present study, we demonstrated that selective activation of M1 mAChRs promoted extinction of initial learned response and facilitated acquisition of reversal learning in the Morris water maze, a behavior test that is mainly dependent on the hippocampus. However, these effects were abolished in GluA2 mutant mice with deficiency in phosphorylation of Ser880 by protein kinase C (PKC). Further long-term depression (LTD) in the hippocampal CA1 area induced by M1 mAChR activation was shown to be dependent on AMPA receptor subunit GluA2 but not GluA1. M1 mAChRs increased GluA2 endocytosis through phosphorylation of Ser880 by PKC. Inhibition of PKC blocked M1 mAChR-mediated LTD, memory switching and reversal learning facilitation. Moreover, the slow memory extinction observed in GluA2 mutant mice and PKC inhibitor-treated mice appeared to affect the consolidation and retrieval of reversal learning. Thus, these results demonstrate that M1 mAChRs mainly facilitate acquisition in spatial reversal learning and further elucidate that such an effect is dependent on the phosphorylation of GluA2 by PKC. The study helps clarify the role of M1 mAChRs in cognitive flexibility and may prompt the earlier prevention of cognitive inflexibility. Highlights • M1 mAChRs facilitate the acquisition of reversal learning in the Morris water maze. • M1 mAChRs induce LTD and GluA2 endocytosis dependent on PKC in the hippocampus. • The effect of M1 mAChR can be abolished by GluA2 K882A mutation and PKC inhibitor. • Facilitated reversal learning is not associated with memory extinction. • The study prompts targeting M1 mAChRs to prevent cognitive inflexibility. [ABSTRACT FROM AUTHOR]