From brain to blood: Alternative splicing evidence for the cholinergic basis of mammalian stress responses

Three principal features of mammalian stress responses are that they span peripheral and CNS changes, modify blood cell composition and activities, and cover inter-related alterations in a large number of gene products. The finely tuned spatiotemporal regulation of these multiple events suggests the hierarchic involvement of modulatory neurotransmitters and modified process(es) in the pathway of gene expression that together would enable widely diverse stress responses. We report evidence supporting the notion that acetylcholine (ACh) acts as a stress-response-regulating transmitter and that altered ACh levels are variously associated with changes in the alternative splicing of pre-mRNA transcripts in brain neurons and peripheral blood cells. We used acetylcholinesterase (AChE) gene expression as a case study and developed distinct probes for its alternative splice variants at the mRNA and protein levels. In laboratory animals and human-derived cells, we found stress-induced changes in the alternative splicing patterns of AChE pre-mRNA, which attributes to this gene and its different protein products diverse stress responsive functions that are associated with the enzymatic and noncatalytic properties of AChE. Together, these approaches provide a conceptually unified view of the studied pathways for controlling stress responses in brain and blood.