Premium
Compensatory mechanisms enhance hippocampal acetylcholine release in transgenic mice expressing human acetylcholinesterase
Author(s) -
Erb Christina,
Troost Joachim,
Kopf Silvia,
Schmitt Ulrich,
Löffelholz Konrad,
Soreq Hermona,
Klein Jochen
Publication year - 2001
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2001.00287.x
Subject(s) - acetylcholine , hippocampal formation , acetylcholinesterase , cholinergic , hippocampus , endocrinology , medicine , chemistry , physostigmine , carbachol , muscarinic acetylcholine receptor , microdialysis , striatum , nucleus basalis , spontaneous alternation , cholinergic neuron , neuroscience , biology , biochemistry , central nervous system , receptor , dopamine , enzyme
Central cholinergic neurotransmission was studied in learning‐impaired 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 −8 −10 −3 m neostigmine in the perfusion fluid, 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 significantly lower levels in AChE‐Tg mice as compared with controls. Also, the high‐affinity 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 µg/kg i.p.) normalized all of the enhanced parameters in hAChE‐Tg mice: spontaneous motor activity, hippocampal ACh efflux 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 deficits in mammals with central cholinergic dysfunctions.