M₂Muscarinic Acetylcholine Receptor Knock-Out Mice Show Deficits in Behavioral Flexibility, Working Memory, and Hippocampal Plasticity

Abstract

Muscarinic acetylcholine receptors are known to play key roles in facilitating cognitive processes. However, the specific roles of the individual muscarinic receptor subtypes (M 1 -M 5 ) in learning and memory are not well understood at present. In the present study, we used wild-type (M2 ϩ/ϩ ) and M 2 receptor-deficient (M2 Ϫ/Ϫ mice. Because impaired muscarinic cholinergic neurotransmission is associated with Alzheimer's disease and normal aging processes, these findings should be of considerable therapeutic relevance.

The CCK-system underpins novelty-seeking behavior in the rat: Gene expression and pharmacological analyses

“…Additionally, some evidence suggests that rats with mediodorsal thalamic damage show impaired learning (Beracochea et al, 1989, Harrigan et al, 1991. Among many others participating in learning processes, M2 (Seeger et al, 2004) and 5-HT7 (Meneses, 2004) receptors were selected because their mRNA is densely expressed in the mediodorsal thalamic nuclei (Ballaz et al, 2007b;Vilaro et al, 1992). No other attempts to examine further differences in gene expression were made since it was beyond the scope of the present study.…”

“…This finding is not surprising as there exists evidence of the mediation of acetylcholine muscarinic receptors in the down-stream mechanisms activated by CCK when triggering anxiety (Biró et al, 1997). An increased expression of M2 may be related to the habituation to novel visual stimuli observed in HR rats, since lack of its function produces impaired behavioral flexibility (Seeger et al, 2004). As a result of the exposure to LY225.920, gene expression was altered as a function of phenotype, thereby leading to a collapse of the phenotype differences once the drug was cleared.…”

“…These considerations led us to expand our knowledge of the involvement of CCK in novelty-seeking behavior by using a gene expression and behavioral approach. Additionally, we speculated about a putative interplay between the CCK-system and receptors like 5-HT7 and M2 as they contribute to novelty-seeking behavior and behavioral flexibility respectively (Ballaz et al, 2007b;Seeger et al, 2004).…”

The Role of Acetylcholine in Cocaine Addiction

“…Hippocampal ACh is theorized to facilitate the encoding of new information by simultaneously suppressing excitatory synaptic transmission and enhancing long-term potentiation, while leaving excitatory feed-forward synapses relatively unaffected (Hasselmo et al, 2002). ACh also modulates synaptic plasticity within the hippocampus (Colgin et al, 2003) and long-term potentiation is drastically reduced in genetically engineered mice lacking the mACh M 2 receptor (Seeger et al, 2004).…”

The procholinergic effects of the atypical antipsychotic olanzapine are independent of muscarinic autoreceptor inhibition

“…Besides, scopolamine, as well as genetic invalidation of muscarinic autoreceptors 7,8 result in a profound impairment of cognitive function. In addition, muscarinic autoreceptor agonists rather than antagonists could help not only to control psychotic symptoms 9 but also to invoke functional, whole-spectrum recovery in schizophrenia.…”