Molecular origin(s) of the diverse behavioral responses to anticholinesterases were explored in behaviorally impaired transgenic (Tg) FVB/N mice expressing synaptic human acetylcholinesterase (hAChE-S). Untreated hAChE-S Tg, unlike naïve FVB/N mice, presented variably intense neuronal overexpression of the alternatively spliced, stress-induced mouse 'readthrough' mAChE-R mRNA. Both strains displayed similar diurnal patterns of locomotor activity that were impaired 3 days after a day-to-night switch. However, hAChE-S Tg, but not FVB/N mice responded to the circadian switch with irregular, diverse bursts of increased locomotor activity. In social recognition tests, controls displayed short-term recognition, reflected by decreased exploration of a familiar, compared to a novel juvenile conspecific as well as inverse correlation between social recognition and cortical and hippocampal AChE specific activities. In contrast, transgenics presented poor recognition, retrievable by tetrahydroaminoacridine (tacrine, 1.5 mg kg-1). Tacrine's effect was short-lived (<40 min), suggesting its effect was overcome by anticholinesterase-induced overproduction of mAChE-R. Consistent with this hypothesis, antisense oligonucleotides (two daily intracerebroventricular injections of 25 ng) arrested mAChE-R synthesis, selectively reduced mAChE-R levels and afforded an extended (>24 h) suppression of the abnormal social recognition pattern in transgenics. Efficacy of antisense treatment was directly correlated with AChE-R levels and the severity of the impaired phenotype, being most apparent in transgenics presenting highly abnormal pretreatment behavior. These findings demonstrate that neuronal AChE-R overproduction is involved in various behavioral impairments and anticholinesterase responses, and point to the antisense strategy as a potential approach for re-establishing cholinergic balance.
Bibliographical noteFunding Information:
The authors are grateful to Professor Konrad Löffelholz and Drs Franz-Josef van der Staay (Germany), Menno Pieter Gerkema (The Netherlands) and David Glick (Israel) for discussions and help with experiments. This study was supported by the US-Israel Binational Science Foundation (1999/115), the US Army Medical Research and Development Command (DAMD 17–99– 1-9547) and Ester Neuroscience (to HS). We are particularly grateful to the journal’s reviewers for their instructive and generous comments and help. RY and HS are members of the Eric Roland Center for Neurodegenerative Diseases of The Hebrew University of Jerusalem. CE was the incumbent of a post-doctoral fellowship from the Minerva Foundation.
- Circadian rhythm
- Psychological stress
- Social recognition