Learning and memory impairments in mice lacking the M2 subtype of muscarinic receptor

Abstract

The neurotransmitter acetylcholine is an important modulator of cognitive functions such as learning, memory, and attention. These functions of acetylcholine are mediated by its binding to five distinct subtypes of muscarinic acetylcholine receptor (M1, M2, M3, M4, M5). It is largely unknown which receptor subtypes mediate which functions of acetylcholine because of the lack of availability of subtype-selective drugs. The present study examined the behavioral functions of the M2 subtype of muscarinic receptor by utilizing mice possessing a null-mutation in the gene for M2 (M2KO mice). Assessments of general health and neurological function found no differences between M2KO and wild-type (WT) mice. In assessments of sensory function, M2KO mice showed increased pain sensitivity relative to WT mice in the tail-flick test and decreased dishabituation to a novel odor in an olfactory habituation-dishabituation test. In tests of learning and memory, M2KO mice were impaired in the acquisition (trials to criterion), but not the retention (72 hr) of a passive avoidance task. M2KO mice were impaired in between-sessions, but not within session habituation, and M2KO mice committed more working memory and reference memory errors in a holeboard test of spatial memory function. M2KO mice showed no impairments in either cued or contextual fear conditioning. In summary, the present behavioral data indicate that the M2 receptor is necessary for normal nociception, olfaction, and cognitive function.