title: Pharmacogenetic regulation of acetylcholinesterase activity in Drosophila reveals the regulatory mechanisms of AChE inhibitors in synaptic plasticity.
abstract: We conducted experiments in Drosophila to investigate the consequences of altered acetylcholinesterase (AChE) activity in the nervous system. In ace hypomorphic mutant larvae, the amount of ace mRNA and the activity of AChE both in vivo and in vitro were significantly reduced compared with those of controls. Reduced Ace in Drosophila larvae resulted in significant down-regulation of branch length and the number of boutons in Type 1 glutamatergic neuromuscular junctions (NMJs). These defects in ace hypomorphic mutant larvae were suppressed when Musca domestica AChE was transgenically expressed. Because AChE inhibitors are utilized for medications for Alzheimer's disease, we investigated whether pharmacological inhibition of AChE activity induced any synaptic defects. We found that controls exposed to a sublethal dose of DDVP phenocopied the synaptic structural defects of the ace hypomorphic mutant. These results suggest that down-regulation of AChE activity, regardless of whether it is due to genetic or pharmacological manipulations, results in altered synaptic architecture. Our study suggests that exposure to AChE inhibitors for 6-12 months may induce altered synaptic architectures in human brains with Alzheimer's diseases, similar to those reported here. These changes may underlie or contribute to the loss of efficacy of AChE inhibitors after prolonged treatment.
authors.affiliation: National Academy of Agricultural Science, Rural Development Administration, Suwon 441-707, Republic of Korea.
authors.forename: Wontae
authors.initials: W
authors.lastname: Kim
authors.forename: Daeweon
authors.initials: D
authors.lastname: Lee
authors.forename: Jinkyu
authors.initials: J
authors.lastname: Choi
authors.forename: Ayoung
authors.initials: A
authors.lastname: Kim
authors.forename: Sangmi
authors.initials: S
authors.lastname: Han
authors.forename: Kwanho
authors.initials: K
authors.lastname: Park
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Choi
authors.forename: Jonggil
authors.initials: J
authors.lastname: Kim
authors.forename: Youngcheol
authors.initials: Y
authors.lastname: Choi
authors.forename: Si Hyeock
authors.initials: SH
authors.lastname: Lee
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Koh
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D017931:DNA Primers; D004330:Drosophila / Q000201:enzymology / Q000235:genetics*; D007150:Immunohistochemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009473:Neuronal Plasticity / Q000187:drug effects*; D010597:Pharmacogenetics; D010802:Phylogeny; D011487:Protein Conformation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D013569:Synapses / Q000187:drug effects*
chemical_list: D002800:Cholinesterase Inhibitors; D017931:DNA Primers; D000110:Acetylcholinesterase