Description:
Inhibitors of acetylcholinesterase (AChE) catalysis are increasingly used as insecticides as well as therapeutic and prophylactic agents. However, the long‐term consequences of their use are not yet known. To investigate this topic, we used cultured neurons and transgenic mouse pedigrees that over‐express natural variants of human AChE. Following exposure to an anti‐AChE, alternative splicing of the pre‐mRNA from the single ACHE gene produces the relatively rare AChE‐R mRNA variant in mice and in cultured cerebellar neurons. This promotes a rapid (minutes) yet long‐lasting (weeks) translocation of AChE‐R mRNA into neurites that is associated with extreme neuronal hypersensitivity to both anti‐AChEs and atropine (Meshorer et al. 2002, Science, 295, 508‐512). In transgenic mice, over‐expression of AChE‐R causes stress‐induced irregular bursts of increased locomotor activity and failure of short‐term memory (Cohen et al. Mol. Psych., in press). Nanomolar concentrations of an antisense oligonucleotide selectively suppress AChE‐R mRNA levels in both hyperproducing cultured neurons and mouse brain. Moreover, this treatment reverses the behavioral and cognitive deficits of the mice (effect apparent for > 24 h, vs. < 45 min for tacrine). The efficacy of our antisense experiments raises the possibility of eventually using such agents to achieve AChE variant‐specific suppression, long‐lasting effect, and, presumably, fewer side‐effects than is offered by conventional anticholinesterase therapy.