Altered hippocampal muscarinic receptors in acetylcholinesterase-deficient mice

Laura A. Volpicelli-Daley, Ellen G. Duysen, Oksana Lockridge, Allan I. Levey

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)788-796
Number of pages9
JournalAnnals of Neurology
Volume53
Issue number6
DOIs
StatePublished - Jun 1 2003

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Muscarinic Receptors
Acetylcholinesterase
Cholinesterase Inhibitors
Alzheimer Disease
Down-Regulation
Neuronal Plasticity
Extracellular Signal-Regulated MAP Kinases
Knockout Mice
Dendritic Cells
Cognition
Cholinergic Agents
Hippocampus
Brain
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Altered hippocampal muscarinic receptors in acetylcholinesterase-deficient mice. / Volpicelli-Daley, Laura A.; Duysen, Ellen G.; Lockridge, Oksana; Levey, Allan I.

In: Annals of Neurology, Vol. 53, No. 6, 01.06.2003, p. 788-796.

Research output: Contribution to journalArticle

Volpicelli-Daley, Laura A. ; Duysen, Ellen G. ; Lockridge, Oksana ; Levey, Allan I. / Altered hippocampal muscarinic receptors in acetylcholinesterase-deficient mice. In: Annals of Neurology. 2003 ; Vol. 53, No. 6. pp. 788-796.
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