Compensatory mechanisms enhance hippocampal acetylcholine release in transgenic mice expressing human acetylcholinesterase

Abstract

Central cholinergic neurotransmission was studied in learningimpaired transgenic mice expressing human acetylcholinesterase (hAChE-Tg). Total catalytic activity of AChE was approximately twofold higher in synaptosomes from hippocampus, striatum and cortex of hAChE-Tg mice as compared with controls (FVB/N mice). Extracellular acetylcholine (ACh) levels in the hippocampus, monitored by microdialysis in the absence or presence of 10 28 210 23 M neostigmine in the perfusion¯uid, were indistinguishable in freely moving control and hAChE-Tg mice. Muscarinic receptor functions were unchanged as indicated by similar effects of scopolamine on ACh release and of carbachol on inositol phosphate formation. However, when the mice were anaesthetized with halothane (0.8 vol. %), hippocampal ACh reached signi®cantly lower levels in AChE-Tg mice as compared with controls. Also, the high-af®nity choline uptake (HACU) in hippocampal synaptosomes from awake hAChE-Tg mice was accelerated but was reduced by halothane anaesthesia. Moreover, hAChE-Tg mice displayed increased motor activity in novel but not in familiar environment and presented reduced anxiety in the elevated plus-maze test. Systemic application of a low dose of physostigmine (100 mg/kg i.p.) normalized all of the enhanced parameters in hAChE-Tg mice: spontaneous motor activity, hippocampal ACh ef¯ux and hippocampal HACU, attributing these parameters to the hypocholinergic state due to excessive AChE activity. We conclude that, in hAChE-Tg mice, hippocampal ACh release is up-regulated in response to external stimuli thereby facilitating cholinergic neurotransmission. Such compensatory phenomena most likely play important roles in counteracting functional de®cits in mammals with central cholinergic dysfunctions.

Effects of cochlear ablation on muscarinic acetylcholine receptor binding in the rat cochlear nucleus

“…Several studies have reported changes of muscarinic receptor expression after manipulations that affect cholinergic transmission (Wall et al, 1992(Wall et al, , 1994Inoue et al, 1995;Gunasena et al, 1995;Levey et al, 1995;Harrison et al, 1996;Rouss and Levey, 1997;Erb et al, 2001;Volpicelli-Daley et al, 2003). Although these studies suggest that muscarinic receptor expression levels may be regulated according to the availability of acetylcholine to maintain a homeostatic balance, our results so far suggest increased muscarinic receptor expression without decreased acetylcholine synthetic capacity (Jin et al, 2005).…”

Impairment of reward-related learning by cholinergic cell ablation in the striatum

“…The transgenic mice that overexpressed acetylcholinesterase also showed increase in locomotor activity at the novel environment but not at the familiar environment (25). We examined locomotor activity at the exploratory and habituated phases of cholinergic cell-eliminated transgenic mice.…”

Neuronal overexpression of ‘readthrough’ acetylcholinesterase is associated with antisense-suppressible behavioral impairments

“…Similarly, in a new environment, hAChE-S Tg mice displayed increased locomotor activity as compared with controls. 11 In the social recognition paradigm, they failed to remember a conspecific juvenile, even following a delay interval of only 5 min. This extends previous reports on their spatial learning and memory impairments 9,10 and agrees with previous reports 22,27 on the social behavior changes associated with cholinergic impairments.…”

“…9 Control, nonTg FVB/N mice were obtained by littermate breeding. Adult, [8][9][10][11][12][13][14][15][16][17][18][19][20] wk old Tg and control male mice were housed 4-5 per cage in a 12 h dark/light cycle with free access to food and water. All experiments were conducted during the first half of the dark phase of a reversed 12 h dark/light cycle, under dim illumination.…”