Altered Striatal Function and Muscarinic Cholinergic Receptors in Acetylcholinesterase Knockout Mice

Abstract

Cholinesterase inhibitors are commonly used to improve cognition and treat psychosis and other behavioral symptoms in Alzheimer's disease, Parkinson's disease, and other neuropsychiatric conditions. However, mechanisms may exist that down-regulate the synaptic response to altered cholinergic transmission, thus limiting the efficacy of cholinomimetics in treating disease. Acetylcholinesterase knockout (AChEϪ/Ϫ) mice were used to investigate the neuronal adaptations to diminished synaptic acetylcholine (ACh) metabolism. The striatum of AChEϪ/Ϫ mice showed no changes in choline acetyltransferase activity or levels of the vesicular ACh transporter but showed striking 60% increases in the levels of the highaffinity choline transporter. This transporter takes choline from the synapse into the neuron for resynthesis of ACh. In addition, the striata of AChEϪ/Ϫ mice showed dramatic reductions in levels of the M 1 , M 2 , and M 4 muscarinic ACh receptors (mAChRs), but no alterations in dopamine receptors or the ␤2 subunit of nicotinic receptors. M 1 , M 2 , and M 4 also showed decreased dendritic and cell surface distributions and enhanced intracellular localizations in striatal neurons of AChEϪ/Ϫ mice. mAChR antagonist treatment reversed the shifts in mAChR distribution, indicating that internalized receptors in AChEϪ/Ϫ mice can recover to basal distributions. Finally, AChEϪ/Ϫ mice showed increased sensitivity to mAChR antagonist-induced increases in locomotor activity, demonstrating functional mAChR down-regulation. mAChR downregulation in AChEϪ/Ϫ mice has important implications for the long-term use of cholinesterase inhibitors and other cholinomimetics in treating disorders characterized by perturbed cholinergic function.

Are there non-catalytic functions of acetylcholinesterases? Lessons from mutant animal models

“…AChE À/À mice show drastic reduction of the M1, M2 and M4 mAChR in the cortex and the hippocampus. (93)(94)(95)(96) The subcellular distribution of receptors is also altered: cell surface localization is decreased and the intracellular pool is increased. Treatment with atropine, a muscarinic antagonist that blocks activation of muscarinic receptors, induces a return of M1 receptors to the cell surface.…”

The Butyrylcholinesterase Knockout Mouse as a Model for Human Butyrylcholinesterase Deficiency

“…BChE Ϫ/Ϫ mice were resistant to oxotremorine, but hypersensitive to pilocarpine. Downregulation of all muscarinic receptors, as seen in the AChE Ϫ/Ϫ mouse (Bernard et al, 2003;Chatonnet et al, 2003;Li et al, 2003;Volpicelli-Daley et al, 2003;Adler et al, 2004), would have resulted in resistance to both oxotremorine and pilocarpine. The opposite response to two different muscarinic agonists may be explained by tissue-specific alterations.…”

“…Muscarinic and nicotinic receptor levels are down-regulated in AChE-deficient mice (Li et al, 2003;Volpicelli-Daley et al, 2003;Adler et al, 2004). In this study, receptor function in BChE Ϫ/Ϫ mice was tested using the nicotinic receptor agonist nicotine, and the muscarinic receptor agonists oxotremorine and pilocarpine.…”

Demonstration of nondeclarative sequence learning in mice: Development of an animal analog of the human serial reaction time task: Figure 1.

“…These include many knockout mice probing receptor and transporter function (Centonze et al 2003;Metzger et al 2002;Viggiano et al 2003), models relevant to drug abuse (Phillips 2002;Berrendero et al 2003), and transgenic models of Huntington's disease (Mangiarini et al 1996;Schilling et al 1999), Parkinson's disease (Maguire-Zeiss and Federoff 2003;Li et al 2004), and other basal ganglia disorders (Sriram et al 2002;Orth and Tabrizi 2003;Volpicelli-Daley et al 2003). Despite the enormous amount of work that has been devoted to characterizing the neurophysiological and motor phenotypes of these mice, there is limited information about their cognitive phenotypes, and no procedures have been developed to help determine how nondeclarative learning might be compromised by any developing neurodegenerative phenotype.…”