The researchers, Marco Prado, Marc Caron, Vania Prado, and their colleagues, said their findings reveal a critical role in central nervous system (CNS) function for the component of the reloading machinery, called an acetylcholine transporter, that they knocked out.
They also said their findings suggest that the mouse model will be useful in understanding how defects in neurons that use acetylcholine to trigger one another contribute to cognitive decline in such disorders as Alzheimer's disease (AD) and aging. The researchers published their finding in the September 7, 2006, issue of the journal Neuron, published by Cell Press.
To explore the role of the acetylcholine transporter, the researchers genetically modified mice to either completely lack the transporter gene or to have reduced levels of it. Such transporters normally retrieve acetylcholine that one neuron has used to trigger another and transport it to storage sacs called vesicles that are the reservoir for neurotransmitter for subsequent use. The researchers found that such transporter-deficient mice were less able to fill such vesicles with acetylcholine.
In behavioral tests, the researchers found that the mice with lower levels of the transporter were less able to learn to hang on to a rotating rod than normal mice. Mice completely lacking the transporter were totally unable to manage the task because they lacked physical endurance. Thus, wrote the researchers, those mice might be useful models for studying the effects of reduced acetylcholine release in certain neuromuscular disorders.
Both normal mice and those with reduced transporter were equally able to learn and remember to avoid a mild shock. However, the reduced-transporter mice showed deficits in object recognition--significantly less able to remember that they had encountered specific-shaped plastic blocks before. The altered mice also showed less memory of "intruder" mice placed in their cages--evidence of reduced social recognition.
Significantly, the researchers found that when they used a drug to enhance acetylcholine in the transporter-deficient mice, those mice showed improved performance on social recognition tests, implying that the deficit in social recognition was caused by a reduction in "cholinergic tone."
Prado, Caron, and their colleagues concluded that "Our observations support the notion that reduced cholinergic tone in AD mouse models can indeed cause deficits in social memory. However, based on somewhat similar impairments found in the object and social recognition tasks, it is possible that mild cholinergic deficits may cause a more general memory deficit for recognizing previously learned complex cues, whether social or not. Future detailed investigations will be necessary to further define the specific type of cognitive processing affected by cholinergic deficits in these mutants.
"Such studies in mouse models of reduced cholinergic tone may be particularly informative for understanding the contribution of cholinergic decline to specific behavioral alterations observed in certain pathologies of the CNS and may even be helpful in understanding physiological aging," wrote the researchers.
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