Genetic and Epigenetic Mechanisms Underlying Acute and Delayed Neurodegenerative Consequences of Stress and Anticholinesterase Exposure

摘要

The effect of stress and exposure to anti-cholinesterases on the cholinergic system were tested in vitro and in vivo. Rapid muscle fatigue was identified and electrophysiologically characterized in mice with elevated levels of AChE-S, the synaptic variant of acetylcholinesterase (AChE). Anxiety responses were observed in mice that over-expressed the stress-associated variant, AChE-R. The binding partner of AChE-R in mouse neurons was identified as a component of the protein kinase-C signaling system. The role of AChE-R in the symptoms of experimental myasthenia gravis in rats has been documented. As the response to chronic exposure to organophosphate anticholinesterases provokes a stress-like response from the cholinergic system, the effect of such exposure in humans on electroencephalographic abnormalities and their origin in the brain was studied. Future research will be assisted by the development of an anti- AChE-S polyclonal antibody, and a mouse strain that produces an endogenous anti- AChE-R antisense reagent upon feeding of doxycycline. These experiments are building a case for the involvement of unregulated AChE-R production in long- term stress response.