Muscarinic modulations of neuronal anticholinesterase responses

A. Salmon, C. Erb, E. Meshorer, D. Ginzberg, Y. Adani, I. Rabinovitz, G. Amitai, H. Soreq*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


Anticholinesterases (antiChEs) are increasingly used for treating patients with neurodegenerative diseases, but the dependence of their effects on the integrity of cholinergic functions has not yet been analyzed at the molecular level. Here, we report that manipulation of muscarinic neurotransmission confers drastic changes on antiChE responses in the rat brain. In the brains of naïve, un-stressed rats, the irreversible organophosphate antiChE, diisopropylfluorophosphonate (DFP) induced post-treatment accumulation of catalytically active G1 monomers of acetylcholinesterase (AChE). Pre-treatment with the selective M1 muscarinic antagonist, pirenzepine, but not the general muscarinic antagonist, scopolamine, attenuated this G1 increase. DFP-enhanced AChE gene expression was accompanied by diverted splicing from the primary AChE-S mRNA variant, encoding G4 synaptic membrane AChE-S tetramers, to "readthrough" AChE-R mRNA, which encodes soluble G1 monomers. Both the mRNA increase and the shifted splicing were long lasting (>24 h) and common to the parietal cortex and hippocampal CA1 and CA3 neurons. Importantly, the splicing shift was maximal under DFP alone, as compared with sham-injected rats, and virtually preventable by pre-treatment with pirenzepine. In contrast, induction of AChE transcription was less dependent on muscarinic function, resulting in AChE-S but not AChE-R increases. Our findings demonstrate distinct regulation of the enhanced transcription and the alternative splicing reactions to antiChE treatment and shed new light on the differential responses to antiChEs of demented patients with increasingly impaired cholinergic neurotransmission.

Original languageAmerican English
Pages (from-to)105-113
Number of pages9
JournalChemico-Biological Interactions
StatePublished - 15 Dec 2005

Bibliographical note

Funding Information:
The authors are grateful to Dr. K. Loeffelholz and J. Klein (Mainz) for helpful discussions. This study was supported by the Israel Science Foundation (Grant no. 618/02) and by Ester Neuroscience Ltd. (to H.S.). C. Erb was the incumbent of a Minerva Post-doctoral fellowship for work in Jerusalem.


  • Acetylcholinesterase
  • Alternative splicing
  • Muscarinic receptors
  • Rat brain anticholinesterases


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