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

Central cholinergic neurotransmission was studied in learning-impaired tran sgenic mice expressing human acetylcholinesterase (hAChE-Tg). Total catalyt ic activity of AChE was approximately twofold higher in synaptosomes from h ippocampus, 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 ne ostigmine in the perfusion fluid, were indistinguishable in freely moving c ontrol and hAChE-Tg mice. Muscarinic receptor functions were unchanged as i ndicated 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 le vels in AChE-Tg mice as compared with controls. Also, the high-affinity cho line uptake (HACU) in hippocampal synaptosomes from awake hAChE-Tg mice was accelerated but was reduced by halothane anaesthesia. Moreover, hAChE-Tg m ice displayed increased motor activity in novel but not in familiar environ ment and presented reduced anxiety in the elevated plus-maze test. Systemic application of a low dose of physostigmine (100 mug/kg i.p.) normalized al l of the enhanced parameters in hAChE-Tg mice: spontaneous motor activity, hippocampal ACh efflux and hippocampal HACU, attributing these parameters t o the hypocholinergic state due to excessive AChE activity. We conclude tha t, 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 fu nctional deficits in mammals with central cholinergic dysfunctions.