Abstract
Cholinergic neurons in the basal forebrain play a crucial role in plasticity, memory and vulnerability to neurodegenerative pathologies, such as Alzheimer's disease (AD). Like acetylcholinesterase (AChE), butyrylcholinesterase (BChE) hydrolyses the neurotransmitter acetylcholine ACh, contributing to choline generation and recycling. We here characterized the behavioral phenotypes of heterozygous AChE knockout (hetAChE KO) mice and homozygous BChE KO mice, focusing on memory functions and vulnerability to amyloid toxicity. First, AChE activity was significantly decreased in the hippocampus and cortex of male and female hetAChE KO mice, but BChE activity was preserved. hetAChE KO mice 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 using a ‘sustained acquisition’ protocol (three swim trials per day) or a ‘mild acquisition’ protocol (two swim trials per day) 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 similar for hetAChE KO and wildtype mice. When mice were administered intracerebroventricularly (ICV) an oligomeric amyloid β25–35 peptide, generating AD-like toxicity, they failed to show learning deficits. The peptide also failed to generate oxidative stress in forebrain structures. Second, male and female BChE KO mice tested for place learning in the water-maze showed increased acquisition slopes and presence in the training quadrant during the probe test. An increased passive avoidance response was also observed for males. BChE KO mice therefore showed enhanced learning ability in spatial and non-spatial memory tests. In BChE KO mice, the Aβ25–35-induced deficit in place learning was attenuated in males and blocked in females. No changes in lipid peroxidation or ACh levels were observed after Aβ25–35 treatment in BChE KO mice. We conclude that, on the one hand, the increase in cholinergic tonus observed in hetAChE KO mice did not result in increased memory functions but allowed a significant prevention of the deleterious effects of amyloid toxicity. On the other hand, the genetic invalidation elimination of BChE in mice increased learning capacities and lowered the vulnerability to Aβ toxicity.