Impaired object-location learning and recognition memory but enhanced sustained attention in M2 muscarinic receptor-deficient mice

RATIONALE: Muscarinic acetylcholine receptors are known to play key roles in mediating cognitive processes, and impaired muscarinic cholinergic neurotransmission is associated with normal ageing processes and Alzheimer’s disease. However, the specific contributions of the individual muscarinic receptor subtypes (M1–M5) to cognition are presently not well understood. OBJECTIVES: The aim of this study was to investigate the contribution of M2-type muscarinic receptor signalling to sustained attention, executive control and learning and memory. METHODS: M2 receptor-deficient (M2(−/−)) mice were tested on a touchscreen-operated task battery testing visual discrimination, behavioural flexibility, object-location associative learning, attention and response control. Spontaneous recognition memory for real-world objects was also assessed. RESULTS: We found that M2(−/−) mice showed an enhancement of attentional performance, but significant deficits on some tests of learning and memory. Executive control and visual discrimination were unaffected by M2-depletion. CONCLUSIONS: These findings suggest that M2 activation has heterogeneous effects across cognitive domains, and provide insights into how acetylcholine may support multiple specific cognitive processes through functionally distinct cholinergic receptor subtypes. They also suggest that therapeutics involving M2 receptor-active compounds should be assessed across a broad range of cognitive domains, as they may enhance some cognitive functions, but impair others.