Postnatal developmental delay and supersensitivity to organophosphate in gene-targeted mice lacking acetylcholinesterase

Acetylcholinesterase (AChE; EC 3.1.1.7) is the primary terminator of nerve impulse transmission at cholinergic synapses and is believed to play an imp ortant role in neural development. Targeted deletion of four exons of the A CHE gene reduced AChE activity by half in heterozygous mutant mice and tota lly eliminated AChE activity in nullizygous animals. Butyrylcholinesterase (EC 3.1.1.8) activity was normal in AChE -/- mice. Although nullizygous mic e were born alive and lived up to 21 days, physical development was delayed . The neuromuscular junction of 12-day-old nullizygous animals appeared nor mal in structure. Nullizygous mice were highly sensitive to the toxic effec ts of the organophosphate diisopropylfluorophosphate and to the butyrylchol inesterase-specific inhibitor bambuterol. These findings indicate that buty rylcholinesterase and possibly other enzymes are capable of compensating fo r some functions of AChE and that the inhibition of targets other than AChE by organophosphorus agents results in death.