Altered hippocampal muscarinic receptors in acetylcholinesterase‐deficient mice

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Abstract
A primary therapeutic strategy for Alzheimer's disease includes acetylcholinesterase (AChE) inhibitors with the goal of enhancing cholinergic transmission. Stimulation of muscarinic acetylcholine receptors (mAChRs) by elevated levels of ACh plays a role in the effects of AChE inhibitors on cognition and behavior. However, AChE inhibitors only demonstrate modest symptomatic improvements. Chronic treatment with these drugs may cause mAChR downregulation and consequently limit the treatment efficacy. AChE knockout (−/−) mice were utilized in this study as a model for investigating the effects of selective, complete, and chronic diminished AChE activity on mAChR expression and function. In AChE −/− mice, the M1, M2, and M4 mAChRs showed strikingly 50 to 80% decreased expression in brain regions associated with memory. In addition, mAChRs showed decreased presynaptic, cell surface, and dendritic distributions and increased localization to intracellular puncta. Furthermore, mAChR agonist–induced activation of extracellular signal–regulated kinase, a signaling pathway associated with synaptic plasticity and amyloidogenesis, is diminished in the hippocampus and cortex of AChE −/− mice. Therefore, chronic diminished ACh metabolism produces profound effects on mAChR expression and function. The alterations of mAChRs in AChE −/− mice suggest that mAChR downregulation may contribute to the limited efficacy of AChE inhibitors in Alzheimer's disease treatment. Ann Neurol 2003;53:788–796