Behavioral stress and activated serotonergic neurotransmission induce XBP-1 splicing in the rat brain.

The splicing of 26 nucleotides in the coding region of the X-box binding protein-1 (XBP-1) transcript to generate a mature active transcription factor is a part of the unfolded protein response to intracellular endoplasmic reticulum stress. In this study, we demonstrated that XBP-1 splicing is promptly induced in the rat brain including the hippocampus by both inescapable electric foot shock (IS) and pharmacologically manipulated activation of 5-hydroxytryptamine release in a dose-dependent manner. By administering ketanserin, a 5-hydroxytryptamine 2A antagonist, however, we could only partially block the increased splicing by IS and observed that the splicing was not influenced by lithium carbonate pretreatment. Although it is still unclear whether the enhanced unfolded protein response functions neuroprotectively by modulating the rate of general translation and increasing chaperone proteins or whether it eventually induces cellular damage by triggering apoptosis, the present results indicate the possible existence of a new adaptive intracellular signaling pathway in the brain that responds to environmentally challenged behavioral stress loading.