Learning and memory impairments in a congenic C57BL/6 strain of mice that lacks the M2 muscarinic acetylcholine receptor subtype

Abstract

The neurotransmitter acetylcholine is an important modulator of cognitive functions including attention, learning, and memory. The actions of acetylcholine are mediated by five distinct muscarinic acetylcholine receptor subtypes (M 1 -M 5 ). The lack of drugs with a high degree of selectivity for these subtypes has impeded the determination of which subtypes mediate which components of cholinergic neurotransmission relevant to cognitive abilities. The present study examined the behavioral functions of the M 2 muscarinic receptor subtype by utilizing congenic C57BL/6 mice possessing a null-mutation in the M 2 muscarinic receptor gene (M 2 −/− mice). Comprehensive assessment of general health and neurological function found no major differences between M 2 −/− and wild-type (M 2 +/+ ) mice. In tests of learning and memory, M 2 −/− mice were impaired in the acquisition (trials to criterion), but not the retention (72 hr) of a passive avoidance task. In a novel open field, M 2 −/− mice were impaired in between-sessions, but not within-session habituation. In a holeboard test of spatial memory, M 2 −/− mice committed more errors in working memory than M 2 +/+ mice. Reference memory did not differ between the genotypes. M 2 −/− mice showed no impairments in either cued or contextual fear conditioning. These findings replicate and extend earlier findings in a hybrid strain and solidify the interpretation that the M 2 receptor plays a critical role in specific components of cognitive abilities.

Sleep, activity, temperature and arousal responses of mice deficient for muscarinic receptor M2 or M4

“…Carbamylcholine produces similar concentration-dependent bradycardia in spontaneously beating atria from M4R KO and control mice but not in atria from M2R KO mice (Stengel et al 2000). With regard to centrally mediated functions, M2R KO mice, as compared with genetically intact mice, show numerous cognitive impairments (Bainbridge et al 2008;Degroot et al 2005;Seeger et al 2004;Tzavara et al 2003). Muscarinic receptors also influence endocrine function.…”

An acetylcholinesterase inhibitor, eserine, induces long-term depression at CA3-CA1 synapses in the hippocampus of adult rats

“…For instance, Sheffler and colleagues (2009) report no impairment in hippocampus-dependent learning, due to injection of a highly specific M 1 mAChR antagonist, VU-022035, but allosteric M 1 mAChR agonists enhance acquisition of hippocampus-dependent cognition in another report (Digby et al 2012). Also, whereas disruption of the M 2 gene causes clear behavioral deficits in spatial learning and hippocampal memory tasks (Bainbridge et al 2008;Seeger et al 2004), the injection of M 2 /M 4 -favoring antagonists actually improves cognitive performance in some studies (Aura et al 1997;Baratti et al 1993;Carey et al 2001;Galli et al 2000;Hamm et al 1995;Kopf et al 1998;Ohno et al 1994;Packard et al 1990;Vannucchi et al 1997).…”

Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory

“…Mice lacking the M 4 receptor exhibit normal working and long-term memory (Degroot and Nomikos 2006;Koshimizu et al 2012), although they do have impairments in some social and addiction-like behaviors (de la Cour et al 2015;Koshimizu et al 2012;Schmidt et al 2011). In contrast, M 2 knockout mice have a variety of learning-related phenotypes, such as altered LTP (Seeger et al 2004;Zheng et al 2012), deficits in behavioral flexibility during learning tasks (Seeger et al 2004), impaired working memory, and poor acquisition of a passive avoidance task (Bainbridge et al 2008). However, they do not display any impairment in cued or contextual fear conditioning (Bainbridge et al 2008), suggesting that M 2 /M 4 coactivation might be critical for the observed effect.…”

“…In contrast, M 2 knockout mice have a variety of learning-related phenotypes, such as altered LTP (Seeger et al 2004;Zheng et al 2012), deficits in behavioral flexibility during learning tasks (Seeger et al 2004), impaired working memory, and poor acquisition of a passive avoidance task (Bainbridge et al 2008). However, they do not display any impairment in cued or contextual fear conditioning (Bainbridge et al 2008), suggesting that M 2 /M 4 coactivation might be critical for the observed effect.…”

“…Although pharmacological and electrophysiological approaches often point to M 1 or M 2 as potent mediators of learning (Sen and Bhattacharya 1991;Fornari et al 2000;Power et al 2003;Soares et al 2006;Figueredo et al 2008;Ma et al 2009), constitutive knockout of these receptors has no effect on learning in a variety of tasks (Anagnostaras et al 2003;Bainbridge et al 2008). Moreover, when such manipulations do impact learning, as is the case with constitutive M 3 deletion (Poulin et al 2010), the neuroanatomical basis for the effect and the specific memory process(es) affected remain unknown.…”