Résumé
Acetylcholinesterase (AChE) is the main catabolic enzyme of acetylcholine, responsible for the synaptic clearance of the neurotransmitter from the synaptic cleft. Decrease in AChE expression, or activity, results in increased cholinergic tonus in the brain or periphery, with concomittant regulations of nicotinic and muscarinic receptors expression. We generated AChE knockout mice and characterized the behavioral phenotype of heterozygous animals, particularly focusing on learning and memory functions. Male and female, AChE+/- and AChE+/+ littermate controls (129sv strain), tested at 5-9 weeks of age, failed to show any difference in terms of locomotion, exploration and anxiety parameters in the open-field test. Animals were then tested for place learning in the water-maze. They were trained using a 'sustained acquisition' protocol (3 swims/day during 5 days) or a 'mild acquisition' protocol (2 swims/day during 9 days) to locate an invisible platform in fixed position (reference memory procedure). Then, during 3 days, they were trained to locate the platform in a variable position (working memory procedure). Learning profiles and probe test performances were unchanged in AChE+/- mice as compared with AChE+/+. Mice were then treated with the muscarinic M1 antagonist scopolamine (0.5, 5 mg/kg sc) 20 min before each training session (3 swims/day during 5 days). Scopolamine impaired learning at both doses in AChE+/+ mice, but only at the highest dose in AChE+/- mice. Moreover, the central injection of amyloid beta25-35 peptide (9 nmol) failed to induce learning deficits in AChE+/- mice, contrarily to AChE+/+ controls. These behavioral study shows that the increase in cholinergic tonus did not result in increased memory abilities in these heterozygous AChE+/- mice, but allowed a significant prevention of the deleterious effects of muscarinic blockade or amyloid toxicity.